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WO2017013061A1 - Biomarqueurs associés à des inhibiteurs de lsd1 et utilisations de ceux-ci - Google Patents

Biomarqueurs associés à des inhibiteurs de lsd1 et utilisations de ceux-ci Download PDF

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WO2017013061A1
WO2017013061A1 PCT/EP2016/067053 EP2016067053W WO2017013061A1 WO 2017013061 A1 WO2017013061 A1 WO 2017013061A1 EP 2016067053 W EP2016067053 W EP 2016067053W WO 2017013061 A1 WO2017013061 A1 WO 2017013061A1
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trans
biomarker
subject
level
lsd1
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Tamara Maes
Cristina MASCARÓ CRUSAT
David ROTLLANT POZO
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Oryzon Genomics SA
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Oryzon Genomics SA
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the invention relates to biomarkers associated with LSD1 inhibitors and uses thereof.
  • the invention relates to the use of the biomarkers as disclosed herein to assess target engagement and to follow patient response to treatment.
  • the invention further relates to novel therapeutic uses for LSD1 inhibitors based on said biomarkers.
  • DNA promoter methylation is associated with suppression of gene expression.
  • histones which are proteins, present in the nucleus of eukaryotic cells, that organize DNA strands into nucleosomes by forming molecular complexes around which the DNA winds. Histones play a critical role in modulating chromatin structure and DNA accessibility for replication, repair, and transcription. The covalent modification of histones is closely associated with regulation of gene transcription.
  • Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read' or interpreted by proteins that translate the code into gene expression changes.
  • Histone modifications have been discovered including histone acetylation, histone lysine methylation, histone arginine methylation, histone ubiquinylation, and histone sumoylation.
  • LSD1 Lysine Specific Demethylase-1 (LSD1) (Shi et al. (2004) Cell 119:941) has been reported to be involved in this crucial histone modification.
  • LSD1 has a fair degree of structural similarity, and amino acid identity/homology to polyamine oxidases and monoamine oxidases, all of which (i.e., MAO-A, MAO-B and LSD1) are flavin dependent amine oxidases which catalyze the oxidation of nitrogen-hydrogen bonds and/or nitrogen carbon bonds.
  • LSD1 has been recognized as an interesting target for the development of new drugs to treat cancer, neurological diseases and other conditions, and a number of LSD1 inhibitors are currently under preclinical or clinical development for use in human therapy.
  • Finding pharmacodynamic (PD) biomarkers which indicate that a drug is active can be very valuable for use during clinical trials or in clinical practice.
  • PD biomarkers can be used to monitor target engagement, i.e. to see if the drug is inhibiting the target against which the drug is designed to act in a subject receiving such drug. They can also be used to monitor the response of those patients receiving the drug. If the biomarker indicates that the patient is not responding appropriately to the drug treatment, then the dosage administered can be increased, reduced or treatment can be discontinued. Biomarkers can also be used to identify particular groups of patients that would benefit, or that would benefit the most, from receiving the drug treatment.
  • the invention relates to the identification of biomarkers associated with LSD1 inhibitors and their use.
  • the present invention is based, in part, on the discovery that a set of genes, as described in more detail below, act as PD markers for the activity of LSD1 inhibitors (henceforth "LSD1 i") and are thus useful to monitor the responsiveness of human subjects to LSD1 inhibition.
  • LSD1 i act as PD markers for the activity of LSD1 inhibitors
  • Figure 1 shows the restoration of the discrimination index (Dl) after 2h retention test in female SAMP8 mice when treated for 2 (Fig 1A) and 4 (Fig 1 B) months with compound 1 (Compl ) as described in Example 3.
  • Figure 2 shows the restoration of the discrimination index (Dl) after 2h retention test in male SAMP8 mice when treated for 2 (Fig 2A) and 4 (Fig 2B) months with compound 1 (Compl ) as described in Example 3.
  • Figure 3 shows the restoration of the discrimination index (Dl) after 24h retention test in male SAMP8 mice when treated for 2 (Fig 3A) and 4 (Fig 3B) months with compound 1 (Compl ) as described in Example 3.
  • Figure 4 shows no changes in the platelet blood count of SAMP8 mice treated for 4 months with vehicle or compound 1 (Compl ) as described in Example 3.
  • FIG 5 shows the reduction of S100A9 expression ( ⁇ Cp) in female (Fig 5A) and male (Fig 5B) SAMP8 mice when treated with compound 1 (Compl) as described in Example 5.
  • Figure 6 shows the effects of Compound 1 on Baiap3 expression ( ⁇ Cp) in female (Fig 6A) and male (Fig 6B) SAMP8 mice determined by qRT-PCR as described in Example 12.
  • Figure 7 shows the effects of Compound 1 on Npw expression ( ⁇ Cp) in female (Fig 7A) and male (Fig 7B) SAMP8 mice determined by qRT-PCR as described in Example 12.
  • Figure 8 shows the effects of Compound 1 on Prph expression ( ⁇ Cp) in female (Fig 8A) and male (Fig 8B) SAMP8 mice determined by qRT-PCR as described in Example 12.
  • Figure 9 shows S100A9 mRNA levels ( ⁇ Cp S100A9-GADPH) in human cerebrospinal fluid samples from Alzheimer's disease donors determined as described in Example 13. DETAILED DESCRIPTION OF THE INVENTION
  • the disclosure relates to the analysis of genes that can act as PD markers for LSD1 i and the identification of a group of genes that can be used as such PD markers for monitoring LSD1 inhibition.
  • the expression of S100A9, S100A8, Prph, Npw and Baiap3 has been found to be modulated by treatment with LSD1 inhibitors in vivo.
  • S100A9 and S100A8 have been found to be downregulated by treatment with LSD1 i in vivo in various tissues, including brain. Treatment with LSD1 i also causes upregulation of Prph, Npw and Baiap3 in the brain.
  • these genes are modulated by LSD1 inhibitors irrespective of gender, i.e. they are modulated in the same direction in both males and females.
  • modulation of the expression of these genes by LSD1 i has been confirmed by several techniques, including microarray, RNA sequencing and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCT),as shown in the Examples below.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in the sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • a "change" in the level of the biomarker(s) in relation to S100A9 or S100A8 refers to a decrease in the level of the biomarker(s) as compared to a control, and in relation to Prph, Npw and Baiap3, it refers to an increase in the level of the biomarker(s) as compared to a control.
  • S100A8 and S100A9 are mammalian calcium- and zinc-binding proteins which play a prominent role in the regulation of inflammatory processes and immune response, among others, as disclosed in more detail below.
  • S100A8 also known as S100 Calcium Binding Protein A8, has the following aliases according to GeneCards:
  • S100A9 also known as S100 Calcium Binding Protein A9, has the following aliases according to GeneCards:
  • S100A8 and S100A9 are preferentially found in humans as a S100A8/S100A9 heterodimer (i.e. a dimer formed by the protein monomers S100A8 and S100A9), also known as Calprotectin.
  • Calprotectin S100A8/S100A9 heterodimers can non-covalently pair with one another to form heterotetramers.
  • Prph also known as Peripherin, has the following aliases according to GeneCards:
  • Peripherin is a neuronal intermediate filament protein that is expressed chiefly in motor neurons and other nerve cells that project into the peripheral nervous system. It is not normally expressed in the hippocampus, but can be induced by certain factors and injury/isquemia and may increase plasticity.
  • Npw also known as Neuropeptide W
  • Neuropeptide W has the following aliases according to GeneCards:
  • Npw plays a regulatory role in the organization of neuroendocrine signals accessing the anterior pituitary gland. Stimulates water drinking and food intake. It may play a role in regulating stress responses, emotion, anxiety, and fear.
  • Baiap3 also known as Brain-specific angiogenesis inhibitor associated protein 3, has the following aliases according to GeneCards:
  • Baiap3 is a member of the secretin receptor family. It contains two C2 domains, which are often found in proteins involved in signal transduction or membrane trafficking. Its expression pattern and similarity to other proteins suggest that it may be involved in synaptic functions. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals.
  • Exemplary amino acid sequences and nucleotide sequences of human and murine S100A9, S100A8, Prph, Npw and Baiap3 are shown in the present application in SEQ ID NO: 1 to 20.
  • the biomarkers of the invention relate to the human forms of S100A9, S100A8, Prph, Npw and Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Prph in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Prph in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Prph in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Npw in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Npw in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Npw in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Baiap3 in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, wherein the degree of decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is S100A9 and/or S100A8 in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.
  • the level of the biomarker(s) can be determined using any method known in the art to measure gene expression product levels, including mRNA and protein levels.
  • biomarker which is S100A9 and/or S100A8 encompasses any of S100A9 and/or S100A8 in any of the forms in which they can be found, including without limitation all monomeric forms and all heterodimeric or heterotetrameric forms thereof, such as Calprotectin.
  • determining the level of a biomarker which is S100A9 and/or S100A8 encompasses determining the level of any of S100A9 and/or S100A8 (in any of the forms in which each of them can be found) using any method known in the art to measure gene expression product levels, including mRNA and protein levels.
  • the level of the biomarker(s) can be determined as mRNA. In the methods for monitoring described herein, the level of the biomarker(s) can be determined as protein. In the methods for monitoring according to the present invention, the sample obtained from the subject to be compared to a control can be obtained at different time points, i.e. after the subject has been treated or has received a first, second, third etc dosage of the LSD1 inhibitor.
  • the "subject receiving treatment with an LSD1 inhibitor" i.e.
  • the subject being monitored using the methods for monitoring according to the invention can be either a subject under active treatment with the LSD1 inhibitor or a subject within a treatment break when the treatment with an LSD1 inhibitor may consist of multiple cycles of drug administration separated by break periods during which the subject may also be monitored.
  • control is preferably a sample obtained from the to be monitored subject before the start of the treatment or at an earlier time point.
  • the sample is preferably a peripheral sample.
  • the peripheral sample can be e.g. cerebrospinal fluid (CSF), blood, plasma, serum, stool, saliva, sputum, gingival crevicular fluid, hair follicle or skin biopsy.
  • CSF cerebrospinal fluid
  • the LSD1 inhibitor can be an irreversible LSD1 inhibitor or a reversible LSD1 inhibitor.
  • the LSD1 inhibitor is an irreversible LSD1 inhibitor.
  • the LSD1 inhibitor is preferably a 2- (hetero)arylcyclopropylamino compound.
  • the LSD1 inhibitor is preferably a compound disclosed in WO2010/043721 , WO2010/084160, WO201 1/035941 , WO201 1/042217, WO201 1/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047, WO2014/058071 , WO2010/143582, US2010-0324147, WO201 1/131576, WO2014/084298, WO2014/086790, WO2014/164867, or WO2015/021 128.
  • the LSD1 inhibitor is preferably a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), as described in more detail below. More preferably, the LSD1 inhibitor is a compound of formula (III), (VI), (VIII), (IX), (X), (XI), (XII) or (XIII). Still more preferably, the LSD1 inhibitor is a compound from the lists of examples provided below for compounds of formulae (III), (VI), (VIII), (IX), (X) or (XI).
  • the LSD1 inhibitor is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.
  • the subject is preferably a human.
  • the subject can be a patient or a healthy individual.
  • the subject can be a subject that has a CNS disease.
  • the subject can be a subject that has a neurodegenerative disease, for example Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, or Amyotrophic lateral sclerosis, preferably Alzheimer's disease or Mild Cognitive Impairment.
  • a neurodegenerative disease for example Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, or Amyotrophic lateral sclerosis, preferably Alzheimer's disease or Mild Cognitive Impairment.
  • the subject can be a subject that has a cognitive function related disease, for example dementia (such as vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia), delirium, amnesia, Rett disease, schizophrenia, attention- deficit/hyperactivity disorder, or postoperative cognitive dysfunction.
  • dementia such as vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia
  • delirium amnesia
  • Rett disease schizophrenia
  • attention- deficit/hyperactivity disorder or postoperative cognitive dysfunction.
  • the subject can be a subject that has an autoimmune disease.
  • the autoimmune disease can be an acute or chronic autoimmune neuropathy such as multiple sclerosis.
  • the subject can be a subject that has an infection or a disease caused by an infection, preferably a bacterial infection, a fungal infection, a protozoan infection, an influenza infection, or a disease caused by any of said infections.
  • the subject can be a subject that has cancer.
  • the subject can be a subject that has a cardiovascular disease.
  • the subject is a subject that has a CNS disease.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor, i.e.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor, i.e.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor, i.e.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.
  • the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Prph.
  • the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Prph.
  • the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor, i.e.
  • the method is performed in vitro.
  • the method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Prph.
  • the subject is preferably a human.
  • the subject can be a patient or a healthy individual. If the subject is a patient, preferably it is a patient that has a CNS disease, for example a neurodegenerative disease or a cognitive function related disease such as the ones disclosed above.
  • a CNS disease for example a neurodegenerative disease or a cognitive function related disease such as the ones disclosed above.
  • Avp which targets the MAO-B component of dual LSD1/MAO-B inbibitors since it has been found to be upregulated by treatment with a dual LSD1/MA0-B inhibitor like Compound 1 and with a compound with potent MAO-B inhibitory activity and weak LSD1 inhibitory activity like Compound 2, while not being upregulated by selective LSD1 inhibitors, as discussed in more detail in the Examples.
  • Avp can thus be used as a PD marker for MAO-B inhibitors and dual LSD1/MAO-B inhibitors.
  • Avp also known as Arginine vasopressin, has the following aliases according to Gene Cards:
  • Arginine vasopressin is a posterior pituitary hormone which is synthesized in the supraoptic nucleus and paraventricular nucleus of the hypothalamus. Avp is found predominantly in the hypothalamus, but is also located in other brain regions. Avp influences complex social behavior and emotional states, including, but not limited to, aggression, fear, and anxiety. It is also involved in cognition and affiliative behaviors in human.
  • DNA and protein sequences of human and murine Avp have been previously reported, see GenBank Numbers (NCBI-GenBank Flat File Release 207.0, April 15, 2015) and UniProtKB/Swiss-Prot Numbers (Knowledgebase Release 2015_06) listed below, each of which is incorporated herein by reference in its entirety for all purposes. Such sequences can be used to design procedures for detection of and analysis of the level of Avp by ways known to one skilled in the art.
  • Exemplary amino acid sequences and nucleotide sequences of human and murine Avp are shown in the present application in SEQ ID NO: 21 to 24.
  • the biomarker Avp relates to the human form of Avp.
  • the invention relates to a method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the response of a subject to treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor.
  • the method is performed in vitro.
  • the invention provides a method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject.
  • the method is performed in vitro.
  • the invention provides a method for monitoring the response of a subject to treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor.
  • the method is performed in vitro.
  • a "MAO-B inhibitor”, as used herein, is a compound that inhibits MAO-B (i.e. monoamine oxidase-B).
  • the MAO-B inhibitor is a dual LSD1/MAO-B inhibitor as defined below.
  • the dual LSD1/MAO-B inhibitor is a compound of formula (VIII) as defined below.
  • a particularly preferred dual LSD1/MAO-B inhibitor is (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw, Baiap3 and Avp in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the dual LSD1/MAO-B inhibitor.
  • the method is performed in vitro.
  • the dual LSD1/MAO-B inhibitor is a compound of formula (VIII) as defined below.
  • the dual LSD1/MAO-B inhibitor is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor, comprising (i) administering a dual LSD1/MAO-B to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw, Baiap3 and Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the dual LSD1/MAO-B inhibitor.
  • the dual LSD1/MAO-B inhibitor is a compound of formula (VIII) as defined below. More preferably, the dual LSD1/MAO-B inhibitor is (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.
  • control is preferably a sample obtained from the to be monitored subject before the start of the treatment or at an earlier time point.
  • the level of the biomarker can be determined as mRNA.
  • the level of the biomarker can be determined as protein.
  • the sample is preferably a peripheral sample.
  • the peripheral sample can be e.g. cerebrospinal fluid (CSF), blood, plasma, serum, stool, saliva, sputum, gingival crevicular fluid, hair follicle or skin biopsy.
  • CSF cerebrospinal fluid
  • the subject is preferably a human.
  • the present invention relates to the use of a primer / a primer pair in the in vitro methods of the present invention.
  • he present invention relates to a primer / a primer pair for use in the in vitro methods of the present invention.
  • the primer / primer pair can be used for determining the level of a biomarker which is S100A9, S100A8, Npw Prph and/or Baiap3.
  • the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9 , S100A8, Npw, Prph and/or Baiap3.
  • the present invention relates to the use of a primer / a primer pair for a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 in the in vitro methods of the present invention.
  • the primer / primer pair can, for example, be used in amplifying the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3, or in amplifying a part of the sequence.
  • the primer / a primer pair can, for example, be useful to determine the mRNA level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • primer pair refers normally to a forward primer and a reverse primer that are used to amplify a nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3, or a part of that sequence. It is understood that the forward primer normally binds to the strand that is complementary to the strand that the reverse primer binds to.
  • the present invention relates to an in vitro use of a primer / a primer pair for monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the primer / primer pair is for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the present invention relates to a primer / a primer pair for use in monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the primer / primer pair is for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the present invention relates to the use of a binding molecule in the in vitro methods of the present invention.
  • the present invention relates to a binding molecule for use in the in vitro methods of the present invention.
  • the binding molecule specifically binds to a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 wherein the biomarker is a protein.
  • the binding molecule can be an antibody.
  • the present invention relates to the use of an antibody in the in vitro methods of the present invention.
  • the present invention relates to an in vitro use of a binding molecule specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein for monitoring the response of a subject to treatment with an LSD1 inhibitor.
  • the binding molecule can be for example an antibody.
  • the present invention relates to a binding molecule specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein for use in monitoring the response of a subject to treatment with an LSD1 inhibitor.
  • the binding molecule can be for example an antibody.
  • the present invention relates to the use of a kit in the in vitro methods of the present invention, wherein the kit comprises means and methods for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 in accordance with the present invention.
  • the present invention relates to a kit for use in the in vitro methods of the present invention, wherein the kit comprises means and methods for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 in accordance with the present invention.
  • the kit can, for example, comprise a primer/a primer pair for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the kit can, for example, comprise a binding molecule, such as an antibody, specifically binding to a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3, wherein the biomarker is a protein.
  • the invention provides an in vitro use of a kit comprising a primer / a primer pair for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 for monitoring the response of a subject to treatment with an LSD1 inhibitor.
  • the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the invention provides an in vitro use of a kit comprising a binding molecule specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein for monitoring the response of a subject to treatment with an LSD1 inhibitor.
  • a binding molecule specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein for monitoring the response of a subject to treatment with an LSD1 inhibitor.
  • the binding molecule can be for example an antibody.
  • the invention provides a use of a primer / a primer pair for the preparation of a kit for monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the primer / primer pair is for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.
  • the invention provides a use of a binding molecule for the preparation of a kit for monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the binding molecule is specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein.
  • the binding molecule can be for example an antibody.
  • CNS diseases including neurodegenerative diseases (including Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, and Amyotrophic lateral sclerosis); autism spectrum disease (including autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder); cognitive function related disease (including dementia such as vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia, delirium, amnesia, Rett disease, schizophrenia, attention-deficit/hyperactivity disorder, and postoperative cognitive dysfunction); mood disorders (including anxiety, stress disorder, post-traumatic stress disorder, panic disorder, phobia, mania, depressive disorders such as major depression, recurrent depression and postpartum disorder, bipolar disorders, and obsessive- compulsive disorder); and stroke and lesion-related diseases (including Traumatic Brain Injury, brain ischemia, intracranial hemorrhage,
  • autoimmune diseases including arthritis (including rheumatoid arthritis, psoriatic arthritis, reactive arthritis and juvenile idiopathic arthritis); inflammatory bowel disease (including Crohn's disease and ulcerative colitis); sclerosis (including systemic sclerosis); acute and chronic autoimmune neuropathies (including autoimmune encephalomyelitis and multiple sclerosis); lupus (including lupus erythematosus, glomerulonephritis, and vasculitis); autoimmune pancreas disease (including autoimmune pancreatitis and diabetes mellitus type 1); autoimmune skin diseases (including psoriasis); autoimmune muscle disease (including dermatomyositis, polymyositis, and inclusion body myositis); and Kawasaki disease;
  • arthritis including rheumatoid arthritis, psoriatic arthritis, reactive arthritis and juvenile idiopathic arthritis
  • inflammatory bowel disease including Crohn's disease and ulcerative colitis
  • sclerosis including system
  • infections particularly bacterial, fungal, protozoan and viral infections and diseases caused by said infections: including bacterial infections (for example caused by E. coli, Pneumococcus, Helicobacter pylori, Salmonella, Staphylococcus aureus, Pseudomonas aeruginosa, Ureaplasma parvum, Francisella tularensis, and Porphyromonas gingivalis), and diseases caused by said bacterial infections such as acute bacterial infections (including acute appendicitis, meningitis, caries, gastritis, gastric ulceration, and acne) and sepsis (including Severe sepsis, septic shock, perinatal and neonatal sepsis); fungal infections (for example Candidiasis or Aspergillosis) and diseases caused by said fungal infections, protozoan infections (for example caused by Plasmodium or Trypanomoma cruzi) and diseases caused by said protozoan infections (for example malaria
  • cancer including carcinomas such as colorectal cancer, bladder cancer, prostate cancer, anaplastic thyroid carcinoma, cutaneous squamous cell carcinoma, gastric cancer, lung cancer and breast cancer (including metastatic breast cancer to brain); and sarcomas such as glioma (for example astrocytoma); and
  • cardiovascular diseases including arteriosclerotic vascular disease (including atherosclerosis and atherogenesis), acute coronary syndromes (like myocardial infarction) and vascular injury (including thrombosis, embolism, vasculitis, venous ulcers, and aortic aneurysms).
  • arteriosclerotic vascular disease including atherosclerosis and atherogenesis
  • acute coronary syndromes like myocardial infarction
  • vascular injury including thrombosis, embolism, vasculitis, venous ulcers, and aortic aneurysms.
  • samples for example peripheral samples
  • samples are collected from each subject following standard procedures at different time points, starting with a sample obtained prior to the start of the treatment with the LSD1 inhibitor.
  • Samples are then processed to prepare them for biomarker analysis following standard procedures, and the level of the biomarker(s) of interest, i.e. S100A9, S100A8, Npw, Prph, and/or Baiap3, is determined in each sample by measuring mRNA levels thereof (for example by qRT-PCR) or protein levels thereof (for example by ELISA).
  • expression levels are normalized relative to the expression level of an endogenous reference gene.
  • Said reference gene is selected following standard criteria, typically among housekeeping genes whose expression is unchanged over a wide range of conditions.
  • An example of a suitable endogenous reference gene is GADPH (glyceraldehyde phosphate dehydrogenase, also known as GAPDH), as disclosed in the Examples.
  • GADPH glycosydehyde phosphate dehydrogenase
  • a standard curve obtained using samples with known concentrations of the target protein can be used to quantify the concentration of target protein in the test sample.
  • CSF samples are collected by lumbar puncture using standard procedures in participating healthcare facilities. Typically, a CSF volume ranging from 1 to 10 mL is obtained from each subject.
  • Fresh CSF samples are processed by centrifugation in order to obtain cell pellets and supernatant, which can either be analyzed then or be frozen and maintained at -80°C until further analysis.
  • Cell pellets can be used to obtain RNA to analyze S100A9, S100A8, Npw, Prph and/or Baiap3 expression levels using methods as described herein, for example by qRT-PCR.
  • Liquid supernatant can be used to analyze S100A9, S100A8, Npw, Prph and/or Baiap3 protein levels using methods as described herein, for example by ELISA.
  • S100A9 protein levels can be analyzed as S100A9 monomer and/or S100A8/S100A9 heterodimer protein concentration, for example by ELISA.
  • the invention relates to the following items:
  • a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject.
  • a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.
  • a method for monitoring the response of a subject to treatment with an LSD1 inhibitor comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.
  • a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in the sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject. 5.
  • a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.
  • a method for monitoring the response of a subject to treatment with an LSD1 inhibitor comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.
  • peripheral sample is cerebrospinal fluid (CSF), blood, plasma, serum, urine, stool, saliva, sputum, gingival crevicular fluid, hair follicle or skin biopsy.
  • CSF cerebrospinal fluid
  • LSD1 inhibitor is a compound disclosed in WO2010/043721 , WO2010/084160, WO201 1/035941 , WO201 1/042217, WO201 1/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047, WO2014/058071 , WO2010/143582, US2010-0324147, WO201 1/131576, WO2014/084298, WO2014/086790, WO2014/164867, or WO2015/021 128.
  • LSD1 inhibitor is a compound of formula (I), (II), (III), (IV), (V). (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII).
  • LSD1 inhibitor is 4-((4-((((1 R,2S)-2- phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid or a pharmaceutically acceptable salt or solvate thereof.
  • the CNS disease is a neurodegenerative disease (e.g. Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, and Amyotrophic lateral sclerosis); an autism spectrum disease (e.g. autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder); a cognitive function related disease (e.g.
  • a neurodegenerative disease e.g. Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, and Amyotrophic lateral sclerosis
  • an autism spectrum disease e.g. autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder
  • a cognitive function related disease e.g.
  • dementia such as vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia, delirium, amnesia, Rett disease, schizophrenia, attention-deficit/hyperactivity disorder, and postoperative cognitive dysfunction); a mood disorder (e.g. anxiety, stress disorder, post-traumatic stress disorder, panic disorder, phobia, mania, depressive disorders such as major depression, recurrent depression and postpartum disorder, bipolar disorders, and obsessive-compulsive disorder); stroke or a lesion-related disease (e.g. Traumatic Brain Injury, brain ischemia, intracranial hemorrhage, intracranial aneurysm, and Cerebral Amyloid Angiopathy).
  • a mood disorder e.g. anxiety, stress disorder, post-traumatic stress disorder, panic disorder, phobia, mania, depressive disorders such as major depression, recurrent depression and postpartum disorder, bipolar disorders, and obsessive-compulsive disorder
  • any of items 1 to 24, wherein the subject has a neurodegenerative disease preferably Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, or Amyotrophic lateral sclerosis, more preferably Alzheimer's disease or Mild Cognitive Impairment.
  • a neurodegenerative disease preferably Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, or Amyotrophic lateral sclerosis, more preferably Alzheimer's disease or Mild Cognitive Impairment.
  • a cognitive function related disease preferably a dementia (e.g. vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia), delirium, amnesia, Rett disease, schizophrenia, attention-deficit/hyperactivity disorder, or postoperative cognitive dysfunction.
  • a dementia e.g. vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia
  • delirium e.g. vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia
  • amnesia e.g. vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia
  • delirium e.g. vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia
  • amnesia e.g. vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia
  • amnesia e
  • the autoimmune disease is arthritis (e.g. rheumatoid arthritis, psoriatic arthritis, reactive arthritis or juvenile idiopathic arthritis); inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis); sclerosis (e.g. systemic sclerosis); an acute or chronic autoimmune neuropathy (e.g. autoimmune encephalomyelitis or multiple sclerosis); lupus (e.g. lupus erythematosus, glomerulonephritis, or vasculitis); an autoimmune pancreas disease (e.g. autoimmune pancreatitis or diabetes mellitus type 1); an autoimmune skin disease (e.g. psoriasis); an autoimmune muscle disease (e.g. dermatomyositis, polymyositis, or inclusion body myositis); or Kawasaki disease.
  • arthritis e.g. rheumatoid arthritis, psoriatic arthritis, reactive arthritis or
  • autoimmune disease is an acute or chronic autoimmune neuropathy (e.g. autoimmune encephalomyelitis or multiple sclerosis).
  • the infection is a bacterial infection (e.g. caused by E. coli, Pneumococcus, Helicobacter pylori, Salmonella, Staphylococcus aureus, Pseudomonas aeruginosa, Ureaplasma parvum, Francisella tularensis, and Porphyromonas gingivalis) or a disease caused by a bacterial infection such as an acute bacterial infection (e.g. acute appendicitis, meningitis, caries, gastritis, gastric ulceration, and acne) or sepsis (e.g.
  • a bacterial infection e.g. caused by E. coli, Pneumococcus, Helicobacter pylori, Salmonella, Staphylococcus aureus, Pseudomonas aeruginosa, Ureaplasma parvum, Francisella tularensis, and Porphyromonas gingivalis
  • Severe sepsis Severe sepsis, septic shock, perinatal or neonatal sepsis
  • a fungal infection e.g. Candidiasis or Aspergillosis
  • a disease caused by a fungal infection e.g. a protozoan infection (e.g. caused by Plasmodium or Trypanomoma cruzi) or a disease caused by a protozoan infection (e.g. malaria or Chagas' disease)
  • a viral infection e.g. influenza virus
  • a disease caused by a viral infection e.g. Influenza
  • the cancer is a carcinoma, preferably colorectal cancer, bladder cancer, prostate cancer, anaplastic thyroid carcinoma, cutaneous squamous cell carcinoma, gastric cancer, lung cancer or breast cancer (including metastatic breast cancer to brain); or a sarcoma, preferably glioma (e.g. astrocytoma).
  • a carcinoma preferably colorectal cancer, bladder cancer, prostate cancer, anaplastic thyroid carcinoma, cutaneous squamous cell carcinoma, gastric cancer, lung cancer or breast cancer (including metastatic breast cancer to brain); or a sarcoma, preferably glioma (e.g. astrocytoma).
  • cardiovascular disease is arteriosclerotic vascular disease (e.g. atherosclerosis and atherogenesis), acute coronary syndromes (e.g. myocardial infarction) or vascular injury (e.g. thrombosis, embolism, vasculitis, venous ulcer, or aortic aneurysm
  • arteriosclerotic vascular disease e.g. atherosclerosis and atherogenesis
  • acute coronary syndromes e.g. myocardial infarction
  • vascular injury e.g. thrombosis, embolism, vasculitis, venous ulcer, or aortic aneurysm
  • a method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject.
  • a method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject.
  • a method for monitoring the response of a subject to treatment with a MAO-B inhibitor comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor.
  • a method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject.
  • a method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject.
  • a method for monitoring the response of a subject to treatment with a MAO-B inhibitor comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor.
  • a method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor comprising determining the level of one or more biomarkers selected from the group consisting of S100A9,
  • a method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor comprising (i) administering a dual LSD1/MAO-B to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw, Baiap3 and Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the dual LSD1/MAO-B inhibitor.
  • determining the level of a biomarker in a sample is used interchangeably with determining or measuring the level of gene expression of the biomarker in the sample.
  • the level of a biomarker in a sample can be determined by any suitable method known in the art to measure gene products, including mRNA and protein. Non-limiting examples of such methods include detecting the quantity of mRNA transcribed from the gene, the quantity of cDNA produced from the reverse transcription of the mRNA transcribed from the gene, or the quantity of protein encoded by the gene.
  • mRNA from a sample can be directly used in determining the level of the biomarker.
  • the level can be determined by hybridization.
  • the RNA can be transformed into cDNA (complementary DNA) copy using methods known in the art.
  • Methods for detecting can include but are not limited to quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), gene expression analyses, microarray analyses, gene expression chip analyses, hybridization techniques and chromatography as well as any other techniques known in the art, e.g. those described in Ralph Rapley, "The Nucleic Acid Protocols Handbook", published 2000, ISBN: 978-0-89603-459-4.
  • Methods for detecting DNA can include but are not limited to PCR, real-time PCR, digital PCR, hybridization, microarray analyses, as well as any other techniques known in the art, e.g. those described in Leland et al, "Handbook of Molecular and cellular Methods in Biology and Medicine", published 2011 , ISBN 9781420069389.
  • the method can comprise detecting the protein expression level of a biomarker.
  • Any suitable methods of protein detection, quantization and comparison can be used, such as those described in John M. Walker, "The Protein Protocols Handbook", published 2009, ISBN 978-1-59745-198-7.
  • the protein expression level of a biomarker can be detected by immune assays which include the recognition of the protein or protein complex by anti antibody or antibody fragment, comprising but not limited to enzyme linked immunosorbent assays (ELISA), "sandwich” immunoassays, immunoradiometric assays, in situ immunoassays, alphaLISA immunoassays, protein proximity assays, proximity ligation assay technology (e.g.
  • Immunoassays may be homogeneous assays or heterogeneous assays.
  • the immunological reaction usually involves the specific antibody, a labeled analyte, and the sample of interest.
  • the signal arising from the label is modified, directly or indirectly, upon the binding of the antibody to the labeled analyte. Both the immunological reaction and detection of the extent thereof can be carried out in a homogeneous solution.
  • Immunochemical labels which may be employed include free radicals, radioisotopes, fluorescent dyes, enzymes, bacteriophages, or coenzymes.
  • the reagents are usually the sample, the antibody, and means for producing a detectable signal.
  • the antibody can be immobilized on a support, such as a bead, plate or slide, and contacted with the specimen suspected of containing the antigen in a liquid phase.
  • the support is then separated from the liquid phase and either the support phase or the liquid phase is examined for a detectable signal employing means for producing such signal.
  • the signal is related to the presence of the analyte in the sample.
  • Means for producing a detectable signal include the use of radioactive labels, fluorescent labels, or enzyme labels.
  • an antibody to the biomarker of interest can be used.
  • a kit for detection can be used.
  • Such antibodies and kits are available from commercial sources such as EMD Millipore, R&D Systems for biochemical assays, Thermo Scientific Pierce Antibodies, Novus Biologicals, Aviva Systems Biology, Abnova Corporation, AbD Serotec or others.
  • antibodies can also be synthesized by any known method.
  • the term "antibody” as used herein is intended to include monoclonal antibodies, polyclonal antibodies, and chimeric antibodies.
  • Antibodies can be conjugated to a suitable solid support (e.g., beads such as protein A or protein G agarose, microspheres, plates, slides or wells formed from materials such as latex or polystyrene) in accordance with known techniques, such as passive binding.
  • a suitable solid support e.g., beads such as protein A or protein G agarose, microspheres, plates, slides or wells formed from materials such as latex or polystyrene
  • Antibodies as described herein may likewise be conjugated to detectable labels or groups such as radiolabels (e.g., 35 S), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), fluorescent labels (e.g., fluorescein, Alexa, green fluorescent protein, rhodamine), can generated by release of singlet oxygen by phthalocyanine containing beads after irradiation at 680 nM and subsequent absorption and emission of light by acceptor beads containing Europium or Therbium, and oligonucleotide labels. Labels can generate signal directly or indirectly. Signal generated can include fluorescence, radioactivity, luminescence, in accordance with known techniques.
  • radiolabels e.g. 35 S
  • enzyme labels e.g., horseradish peroxidase, alkaline phosphatase
  • fluorescent labels e.g., fluorescein, Alexa, green fluorescent protein, rhodamine
  • Labels can
  • the level of the biomarker is measured either as mRNA using qRT-PCT or as protein using an ELISA assay or a proximity ligation assay technology such as a protein qPCR.
  • an LSD1 inhibitor is a compound which inhibits LSD1. Any LSD1 inhibitor known in the art can be used in the methods and therapeutic uses of the invention. Both irreversible and reversible LSD1 i have been reported. Most LSD1 i reported to date are irreversible LSD1 i, which exert their inhibitory activity by becoming covalently bound to the FAD cofactor within the LSD1 active site and are generally based on a 2- (hetero)arylcyclopropylamino moiety. Some reversible inhibitors of LSD1 have also been reported in the literature (see e.g. DP Mould et al, Med. Res. Rev., 2015,35:586-618. doi:10.1002/med.21334, epub 24-nov- 2014).
  • Non-limiting examples of LSD1 i are disclosed e.g. in: WO2010/043721 , WO2010/084160, WO2011/035941 , WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2010/143582, US2010-0324147, WO2011/022489, WO2011/131576, WO2012/034116, WO2012/135113, WO2013/022047, WO2013/025805, WO2014/058071 , WO2014/084298, WO2014/086790, WO2014/164867,WO2014/205213,WO2015/021128, WO2015/031564, US2015-0065434, WO2007/021839, WO2008/127734, WO2015/089192, CN104119280, CN103961340,
  • the LSD1 i is preferably an irreversible LSD1 L
  • the LSD1 inhibitor is preferably a 2-(hetero)arylcyclopropylamino LSD1 L
  • a "2-(hetero)arylcyclopropylamino LSD1 i" or a "2-(hetero)arylcyclopropylamino compound” means a LSD1 i whose chemical structure comprises a cyclopropyl ring substituted at position 1 with an amino group, which can be optionally substituted, and substituted at position 2 with an aryl or heteroaryl group (wherein the aryl or heteroaryl group can be optionally substituted).
  • the ability of a compound to inhibit LSD1 can be tested in vitro using any method known in the art to determine LSD1 inhibition, for example the method disclosed in Example 1.
  • the LSD1 inhibitor is preferably a 2- (hetero)arylcyclopropylamino LSD1 i as disclosed in any of WO2010/043721, WO2010/084160, WO2011/035941 , WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047, WO2014/058071 , WO2010/143582, US2010-0324147, WO2011/131576, WO2014/084298, WO2014/086790, WO2014/164867, WO2015/021128, WO2014/194280, WO2015/123465, WO2015/123437, WO2015/123424, WO2015/123408, WO2015/156417, or WO2015/181380, the disclosure of each of which is
  • the LSD1 inhibitor can be a compound of formula (I) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • each of R1-R5 is optionally substituted and independently chosen from -H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-heterocyclyl, -L-carbocycle, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thio
  • R6 is chosen from -H and alkyl
  • R7 is chosen from -H, alkyl, and cycloalkyl
  • Rx when present is chosen from -H, alkyl, alkynyl, alkenyl, -L-carbocycle, -L-aryl, -L-heterocyclyl, all of which are optionally substituted;
  • R y when present is chosen from -H, alkyl, alkynyl, alkenyl, -L-carbocycle, -L-aryl, -L-heterocyclyl, all of which are optionally substituted;
  • Rz when present is chosen from -H, alkoxy, -L-carbocyclic, -L-heterocyclic, -L-aryl, wherein the aryl, heterocyclyl, or carbocycle is optionally substituted;
  • the LSD1 inhibitor can be a compound of formula (II) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutic thereof:
  • each of R1-R5 is independently chosen from -H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl,
  • R6 is chosen from -H and alkyl
  • R7 is chosen from -H, alkyl, and cycloalkyl
  • R8 is a -L-heterocyclyl wherein the ring or ring system of said -L-heterocyclyl has from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cydoalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyi, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulf
  • R8 is -L-aryl wherein the ring or ring system of said -L-aryl has from 1-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cydoalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyi, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl
  • each L is independently chosen from -(CH 2 )n-(CH 2 )n-, -(CH 2 )nNH(CH 2 )n-, -(CH 2 ) n O(CH 2 ) n -, and -(CH 2 ) n S(CH 2 ) n -, and where each n is independently chosen from 0, 1 , 2, and 3.
  • the LSD1 inhibitor can be a compound of formula (III) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • (A) is heteroaryl or aryl
  • each ( ⁇ '), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyi, cycloalkyi, haloalkoxy, and cyano, wherein each ( ⁇ ') is substituted with 0, 1 , 2, or 3 substituents independently chosen from halo, haloalkyi, aryl, arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, amido, and sulfinyl;
  • X is O, 1, 2, or 3;
  • (B) is a cydopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);
  • (L) is chosen from -CH 2 CH 2 -, -CH2CH2CH2-, and -CH2CH2CH2CH2-;
  • (D) is chosen from -N(-R1)-R2, -0-R3, and -S-R3, wherein:
  • R1 and R2 are mutually linked to form a heterocyclic ring together with the nitrogen atom that R1 and R2 are attached to, wherein said heterocyclic ring has 0, 1 , 2, or 3 substituents independently chosen from -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-Ce alkyl), alkyl, halo, cyano, alkoxy, haloalkyi, and haloalkoxy, or
  • R1 and R2 are independently chosen from -H, alkyl, cydoalkyi, haloalkyi, and heterocydyl, wherein the sum of substituents on R1 and R2 together is 0, 1, 2, or 3, and the substituents are independently chosen from -NH2, -NH(Ci-C 6 alkyl), -N(0-C 6 alkyl)(Ci-C 6 alkyl), and fluoro; and
  • R3 is chosen from -H, alkyl, cydoalkyi, haloalkyi, and heterocydyl, wherein R3 has 0, 1, 2, or 3 substituents independently chosen from -NH 2 , -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), and fluoro.
  • the compound of formula (III) is a compound from the list below:
  • the LSD1 inhibitor can be a compound of formula (IV) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • each ( ⁇ '), if present, is indepedently chosen from aryl, arylalkoxy, arylalkyi, heterocyclyl, aryloxy, halo, alkoxy, haloalkyi, cycloalkyi, haloalkoxy, and cyano, wherein each ( ⁇ ') is substituted with 0, 1, 2 or 3 substituents independently chosen from halo, haloalkyi, aryl, arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, sulfinyl, and carboxamide;
  • X is O, 1, 2, or 3;
  • (B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);
  • (L) is -(CH2)mCRiR2-, wherein m is 0, 1, 2, 3, 4, 5, or 6, and wherein Ri and R2 are each independently hydrogen or C1-C6 alkyl;
  • the compound of formula (IV) is a compound from the list below:
  • the LSD1 inhibitor can be a compound of formula (V) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • X 1 and X 2 are independently C(R2) or N;
  • X 3 and X 4 when present, are independently C(R2) or N;
  • (G) is a cyclyl group
  • each (R1) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L1 -cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl;
  • each (R2) is independently chosen from -H, alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl, wherein each (R2) group has 1 , 2, or 3 independently chosen optional substituents or two (R2) groups can be taken together to form a heterocyclyl or aryl group having 1 , 2, or 3 independently chosen optional substituents, wherein said optional substituents are independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocycly
  • R3 is -H or a (Ci-Ce)alkyl group
  • each L1 is independently alkylene or heteroalkylene
  • n 0, 1, 2, 3, 4 or 5.
  • the compound of formula (V) is a compound from the list below:
  • the LSD1 inhibitor can be a compound of formula (VI) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • (A) is heteroaryl or aryl
  • X is O, 1, 2, or 3;
  • (B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);
  • (L) is chosen from a single bond, -CH 2 -, -CH2CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-;
  • (D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1 , 2, or 3 substituents independently chosen from -NH 2 , -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(CrC6 alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy.
  • (A) is aryl or heteroaryl.
  • Said aryl is preferably phenyl.
  • Said heteroaryl is preferably pyridinyl, pyrimidinyl, or thiophenyl; and/or
  • ( ⁇ ' ), if present, is aryl or arylalkoxy.
  • Said aryl is preferably phenyl.
  • Said arylalkoxy is preferably benzyloxy, all of which can be optionally substituted as provided above; and/or
  • the compound of formula (VI) is a compound from the list below:
  • the LSD1 inhibitor can be a compound of formula (VII) or
  • X 1 and X 2 are each independently C(R2) or N;
  • X 3 and X 4 when present, are each independently C(R2) or N;
  • L1 is -NH- or -NH-CH 2 -;
  • G is a cyclyl group
  • each R1 is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl;
  • each R2 is independently chosen from -H, alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl, wherein each R2 group has 1 , 2, or 3 independently chosen optional substituents, and further wherein two R2 groups bound to adjacent carbon atoms can be taken together to form a heterocyclyl or aryl group having 1 , 2, or 3 independently chosen optional substituents; wherein said optional substituents are each independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylal
  • R3 is -H or an (C1-C6)alkyl group
  • each L2 is independently chosen from alkylene or heteroalkylene
  • n 0, 1, 2, 3, 4 or 5.
  • the compound of formula (VII) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred.
  • the compound of formula (VII) is a compound from the list below: 5-((trans)-2-aminocyclopropyl)-N-(3-chlorophenyl)pyridin-2-amine;
  • the LSD1 inhibitor can be a compound of formula (VIII) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • (A) is a cyclyl group having n substituents (R3);
  • (B) is a cyclyl group or an -(U)-cyclyl group, wherein said cyclyl group or the cyclyl moiety comprised in said -(U)-cyclyl group has n substituents (R2);
  • (L1) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene;
  • (D) is a heteroaryl group or an -(L2)-heteroaryl group, wherein said heteroaryl group or the heteroaryl moiety comprised in said -(L2)-heteroaryl group has one substituent (R1), and further wherein said heteroaryl group is covalently bonded to the remainder of the molecule through a ring carbon atom or the heteroaryl moiety comprised in said -(L2)-heteroaryl group is covalently bonded to the (L2) moiety through a ring carbon atom;
  • (L2) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene;
  • each (R2) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea;
  • each (R3) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea; and
  • n is independently 0, 1 , 2, 3 or 4.
  • (A) is aryl or heteroaryl.
  • Said aryl is preferably phenyl.
  • Said heteroaryl is preferably pyridinyl, and/or;
  • (B) is -0-CH2-phenyl or phenyl, each of which can be optionally substituted with n substituents R2, and/or;
  • (D) is a monocyclic heteroaryl, preferably thiazolyl, oxadiazolyl or pyrimidinyl, and more preferably oxadiazolyl; and/or;
  • (R1) is -NH 2 or -NHCH 3 and more preferably -NH 2 .
  • the compound of formula (VIII) is a compound from the list below:
  • the compound of formula (VIII) is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, or a pharmaceutically acceptable salt thereof.
  • the LSD1 inhibitor can be a compound of formula (IX) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • A is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 1 ;
  • B is hydrogen, R 1 or -L-E
  • E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ;
  • L is a bond, -0-, -NH-, -N(Ci-4 alkyl)-, C1-4 alkylene or heteroCi-4 alkylene;
  • D is a cycloalkyi group having from 4 to 7 C atoms, wherein said cycloalkyi group has one or two substituents R 3 and is further optionally substituted with one or more R 4 , and wherein the cycloalkyi group optionally:
  • (a) is fused to a phenyl or a 5- or 6-membered aromatic heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S, wherein said fused phenyl or said fused aromatic heterocyclic ring is optionally substituted with one or more R 5 ; or
  • (b) is bonded to a linker group -(C(R a )2) P - linking together any two non-adjacent ring carbon atoms of the cycloalkyi group, wherein p is 1 or 2 and each R a independently is hydrogen or C1-4 alkyl; or
  • (c) is linked to a second ring that is either a 3- to 7-membered saturated carbocyclic ring or a 3- to 7-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S, wherein said second ring is linked together with the cycloalkyi group via a single carbon atom common to both rings, and wherein said second ring is optionally substituted with one or more R 6 ;
  • each R 1 is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-8 alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1-8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;
  • each R 2 is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;
  • each R 3 is independently selected from -NR 7 R 8 , -NHOH, -NR 9 COR 10 , -NR 9 S0 2 R 1 °, -NR 9 COOR 10 , - NR 9 CONR 7 R «, -NR S0 2 NR 7 R «, -OH, -CONR 7 R 8 oxo, -C 1 .
  • each R 4 and each R 6 is independently selected from Ci-e alkyl, halo, haloCi-e alkyl, haloCi-e alkoxy and Ci-e alkoxy;
  • each R 5 is independently selected from Ci-e alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;
  • each R 7 and each R 8 is independently selected from hydrogen, C1.8 alkyl, R 2 R 3 N-Ci-8 alkyl and hydroxyC-i-e alkyl, or R 7 and R 8 are linked together to form, along with the N atom to which they are bound, a saturated 3- to 7-membered heterocyclic ring which optionally contains one further heteroatom selected from N, 0 and S, wherein one or more C atoms in said heterocyclic ring are optionally oxidized to form CO groups, wherein one or more S atoms in said heterocyclic ring, if present, are optionally oxidized to form independently SO groups or SO2 groups, and wherein said heterocyclic ring is optionally substituted with one or more R 11 ;
  • each R 9 is independently selected from hydrogen and C1-4 alkyl
  • each R 10 is independently selected from Ci-e alkyl, haloCi-e alkyl, cyclyl and cyclylC -s alkyl, wherein said cyclyl or the cyclyl moiety comprised in said cyclylCi-s alkyl is optionally substituted with one or more R 14 ;
  • each R 11 is independently selected from C1.8 alkyl, halo, C1.8 alkoxy, hydroxyl and -NR 12 R 13 ;
  • each R 12 and each R 13 is independently selected from hydrogen and Ci-e alkyl
  • each R 14 is independently selected from Ci-e alkyl, C2-8 alkenyl, C2-8 alkynyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, O-carboxy, C- carboxy, carbamate and urea; and
  • each R w , R x , Ry and R z is independently selected from hydrogen, halo and C1-4 alkyl.
  • (A) is phenyl, thiazolyl or pyridyl, preferably phenyl, which rings can be optionally substituted with one or more R 1 , and/or
  • (B) is H , and/or
  • R 1 is C1-8 alkyl, amino, amido, hydroxyl, halo, haloCi-e alkyl, haloCi-ealkoxy, cyano, sulfonamide, C1.8 alkoxy, acyl, carboxyl, carbamate, and urea, and more preferably halo, Cu alkyl, haloCi-4 alkyl, Cu alkoxy and C3-6 cycloalkyl; and/or
  • (D) is selected from D1 , D2, D3 and D4:
  • R 3 is selected from -NR R 8 , -NHOH, -NR 9 COR 10 , -NR 9 S0 2 R 1 °, -NR COOR 10 , -NR CONR R 8 , -NR S0 2 NR R 8 , -OH, -CONR 7 R 8 oxo, -C1-4 alkylene-NR 7 R 8 , -C1-4 alkylene-OH and -C1-4 alkylene-CONR 7 R 8 , more preferably from -NR 7 R 8 , -OH, -Ci- 4 alkylene-NR 7 R 8 , and -C1-4 alkylene-OH, still more preferably -NR 7 R 8 (such as -NH 2 ); and/or
  • each R w , R x , R ⁇ and R z is hydrogen.
  • the compound of formula (IX) is a compound from the list below:
  • the compound of formula (IX) is (trans)-N1-((1 R,2S)-2-phenylcyclopropyl)cyclohexane- 1 ,4-diamine; or a pharmaceutically acceptable salt thereof.
  • the LSD1 inhibitor can be a compound of formula (X) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmace thereof:
  • A is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 1 ;
  • B is H, R 1 or -L 1 -E;
  • E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ;
  • L 1 is a bond, -0-, -NH-, -N(Ci-4 alkyl)-, C1-4 alkylene or heteroCi- 4 alkylene;
  • L 2 is a bond and D is a cyclic group selected from:
  • polycyclic ring system which comprises at least one saturated heterocyclic ring, wherein the polycyclic ring system contains from 1 to 4 heteroatoms independently selected from N, 0 and S,
  • one or more ring C atoms in the cyclic group (i) or (ii) are optionally oxidized to form CO groups
  • one or more S atoms in the cyclic group (i) or (ii), if present, are optionally oxidized to form independently SO groups or SO2 groups
  • cyclic group (i) or (ii) is optionally substituted with one or more R 3 ; or L 2 is C1-4 alkylene and D is a cyclic group selected from:
  • polycyclic saturated ring system which comprises at least one heterocyclic ring, wherein the polycyclic saturated ring system contains from 1 to 4 heteroatoms independently selected from N, 0 and S,
  • one or more ring C atoms in the cyclic group (iii) or (iv) are optionally oxidized to form CO groups, wherein one or more S atoms in the cyclic group (iii) or (iv), if present, are optionally oxidized to form independently SO groups or SO2 groups, and
  • each R 1 is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-8 alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1-8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;
  • each R 2 is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;
  • each R 3 is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea; and
  • each R w , R x , Ry and R z is independently selected from hydrogen, halo and C1-4 alkyl.
  • (A) is phenyl, thiazolyl or pyridyl, preferably phenyl, which rings can be optionally substituted with one or more R 1 , and/or
  • R 1 is C1-8 alkyl, amino, amido, hydroxyl, halo, haloCi-e alkyl, haloCi-ealkoxy, cyano, sulfonamide, C1.8 alkoxy, acyl, carboxyl, carbamate, and urea and more preferably halo, Cu alkyl, haloCi-4 alkyl, Cu alkoxy and C3-6 cycloalkyl; and/or
  • L 2 is a bond and (D) is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N, 0 and S wheren D is linked to the remainder of the compound of formula (X) through a C, more preferably a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 N atom wherein D is linked to the remainder of the compound of formula (X) through a C, and even more preferably D is 4- piperidinyl, or L 2 is a bond and (D) is a ring system selected from (a), (b), (c) and (d)
  • any D is optionally substituted with one or more R 3 ;
  • each R w , R x , R ⁇ and R z is hydrogen.
  • the compound of formula (X) is a compound from the list below:

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Abstract

L'invention concerne des biomarqueurs associés à des inhibiteurs de LSD1 et leur utilisation pour évaluer l'engagement de cible et suivre la réponse du patient à un traitement.
PCT/EP2016/067053 2015-07-17 2016-07-18 Biomarqueurs associés à des inhibiteurs de lsd1 et utilisations de ceux-ci Ceased WO2017013061A1 (fr)

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WO2018083138A1 (fr) * 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Biomarqueurs pharmacodynamiques pour traitement du cancer personnalisé à l'aide d'agents de modification épigénétique
WO2018083189A1 (fr) * 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Biomarqueurs pour déterminer la sensibilité à des inhibiteurs de lsd1
WO2018221555A1 (fr) * 2017-05-31 2018-12-06 大鵬薬品工業株式会社 Méthode de prédiction de l'effet thérapeutique d'un inhibiteur de lsd1 en fonction de l'expression d'insm1
US10221125B2 (en) 2015-05-06 2019-03-05 Oryzon Genomics, S.A. Solid forms
US10265279B2 (en) 2016-03-15 2019-04-23 Oryzon Genomics, S.A. Combinations of LSD1 inhibitors for use in the treatment of solid tumors
US10329256B2 (en) 2011-10-20 2019-06-25 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
WO2019211491A1 (fr) * 2018-05-04 2019-11-07 Oryzon Genomics, S.A. Formulation pharmaceutique stable
US10723742B2 (en) 2015-11-27 2020-07-28 Taiho Pharmaceutical Co., Ltd. Biphenyl compound or salt thereof
US10780081B2 (en) 2016-06-10 2020-09-22 Oryzon Genomics, S.A. Method of treating multiple sclerosis employing a LSD1-inhibitor
US11013698B2 (en) 2016-03-15 2021-05-25 Oryzon Genomics S.A. Combinations of LSD1 inhibitors for the treatment of hematological malignancies
US11479563B2 (en) 2017-05-26 2022-10-25 Taiho Pharmaceutical Co., Ltd. Biphenyl compound or salt thereof
US11510915B2 (en) 2017-05-26 2022-11-29 Taiho Pharmaceutical Co., Ltd. Anti-tumor effect potentiator using novel biphenyl compound
RU2789449C2 (ru) * 2017-05-31 2023-02-03 Тайхо Фармасьютикал Ко., Лтд. Способ прогнозирования терапевтического эффекта ингибитора lsd1 на основе экспрессии insm1
US12419858B2 (en) 2019-11-13 2025-09-23 Taiho Pharmaceutical Co., Ltd. Salt of terphenyl compound

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