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WO2010089580A1 - Utilisation d'un inhibiteur de mct1 de traitement du cancer exprimant mct1 sur mct4 - Google Patents

Utilisation d'un inhibiteur de mct1 de traitement du cancer exprimant mct1 sur mct4 Download PDF

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Publication number
WO2010089580A1
WO2010089580A1 PCT/GB2010/050096 GB2010050096W WO2010089580A1 WO 2010089580 A1 WO2010089580 A1 WO 2010089580A1 GB 2010050096 W GB2010050096 W GB 2010050096W WO 2010089580 A1 WO2010089580 A1 WO 2010089580A1
Authority
WO
WIPO (PCT)
Prior art keywords
mctl
methyl
mct4
cancer
patient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2010/050096
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English (en)
Inventor
Susan Elizabeth Critchlow
Lorna Tate
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2010089580A1 publication Critical patent/WO2010089580A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Ci_ 4 alkylsulphonyl Ci_ 4 alkylsulphinyl, carbamoyl, C ⁇ alkylcarbamoyl, di-(Ci_ 4 alkyl)carbamoyl, carboxy, SO 2 N(R 6 )R 7 , p is 1, 2, 3 or 4;
  • the MCT inhibitor is selected from 6-[[3,5-dimethyl-l-(2- pyridinyl)-l/f-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl- 1 -(I -methylethyl)thieno[2,3-d]pyrimidine-2,4- (l/f,3H)-dione (Compound A); 5-[[(45)-4-hydroxy-4-methyl-2- isoxazolidiny 1] carbonyl] -3 -methyl- 1 -( 1 -methylethyl)-6- [ [5 -methyl-3 - (trifluoromethyl)-lH-pyrazol-4-yl]methyl]-thieno[2,3-(i]pyrimidine-2,4(lH,3H)-dione (Compound B); and (45)-4-methyl-2-[[l,2,3,4-te
  • a method of selecting a patient having cancer in need of treatment with an MCTl inhibitor which comprises testing a tumour sample obtained from the patient for selective expression of MCTl over MCT4, MCTl over MCT2 and MCTl over MCT3.
  • a method of identifying a patient having cancer most likely to benefit from treatment with an MCTl inhibitor comprising measuring the expression levels of MCTl, MCT2, MCT3 and MCT4 in a tumour sample obtained from the patient and identifying whether or not the patient is likely to benefit from treatment with an MCTl inhibitor according to the levels present.
  • the expression levels of the monocarboxylate transporters MCTl to MCT4 can be used as a biomarker of susceptibility to effective cancer treatment with an MCTl inhibitor.
  • the tumour is selected from haemological tumours, such as acute myeloid leukemia (AML), and lung, colorectal, gastric, breast and prostate cancer.
  • haemological tumours include, for example, diffuse large B cell lymphoma (DLBCL), Burkitt's lymphoma, B-cell acute lymphoblastic leukemia , chronic myeloid leukemia, B-cell non-hodgkins lymphoma chronic lymphocytic B-leukemia and myeloma.
  • the MCTl inhibitor may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • the PCR step can use a variety of thermostable DNA-dependent DNA polymerases, it typically employs the Taq DNA polymerase, which has a 5 '-3' nuclease activity but lacks a 3 '-5' proofreading endonuclease activity.
  • TAQMAN® PCR typically utilizes the 5 '-nuclease activity of Taq or Tth polymerase to hydro lyse a hybridisation probe bound to its target amplicon, but any enzyme with equivalent 5 ' nuclease activity can be used.
  • Two gene specific oligonucleotide primers are used to generate an amplicon typical of a PCR reaction.
  • 5 '-Nuclease assay data are initially expressed as Ct, or the threshold cycle.
  • Ct the threshold cycle
  • fluorescence values are recorded during every cycle and represent the amount of product amplified to that point in the amplification reaction.
  • the point when the fluorescent signal is first recorded as statistically significant is the threshold cycle (Ct).
  • Ct the threshold cycle
  • PCR is usually performed using an internal standard. The ideal standard is expressed at a constant level among different tissues, and is unaffected by the experimental treatment.
  • RNAs most frequently used to normalise patterns of gene expression are mRNAs for the housekeeping genes glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), 18S, HPRT, and P-actin.
  • PCR primer design Factors considered in PCR primer design include primer length, melting temperature (Tm) , and G/C content, specificity, complementary primer sequences, and 3 '-end sequence.
  • optimal PCR primers are generally 17-30 bases in length, and contain about 20-80%, such as, for example, about 50-60% G+C bases. Tm's between 50 and 80 0 C, e.g about 50 to 70 0 C, are typically preferred.
  • Polyclonal antibodies can be readily generated from a variety of sources, for example, horses, cows, goats, sheep, dogs, chickens, rabbits, mice or rats, using procedures that are well known in the art.
  • antigen is administered to the host animal typically through parenteral injection.
  • various adjuvants may be used to enhance the immunological response against the injected polypeptide.
  • small samples of serum are collected and tested for reactivity to antigen.
  • Such antibodies may be of immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof.
  • Rodent antibodies may be humanised using recombinant DNA technology according to techniques known in the art.
  • Tumour sample immunohistochemistry scoring is performed by a skilled human pathologist and the intensity of staining scored using a 0, +1, +2, +3 (criteria follow) scoring system for the relative staining intensity of the nuclear, cytoplasm and plasma membrane. Score 0, no staining is observed in less than 10% of tumour cells. Score 1+, a faint staining is detected in more than 10% of the tumour cells. Score 2+, a weak to moderate staining is observed in more than 10% of the tumour cells. Score 3+, a moderate to strong staining is observed in more than 10% of the tumour cells.
  • the MCTl polypeptide sequence is disclosed as SEQ ID No.l.
  • the MCT 4 DNA sequence is disclosed as SED ID No. 8.
  • DMSO dimethyl sulphoxide
  • SDS sodium dodecyl sulphate
  • the anti-pro liferative effect of MCTl inhibition was investigated across a broad panel of solid and haematological tumour cell lines.
  • Cells were routinely cultured in their appropriate growth media (according to ATCC cell biology collection guidelines) for between 5-10 passages prior to compound testing.
  • On day 1 between 1000-5000 cells/well were plated into the internal 60 wells of black 96 well plates. lOO ⁇ l Hanks Buffered salt solution (HBSS) was added to the external wells to prevent media evaporation and plates incubated overnight at 37 0 C in the presence of 5% CO 2 .
  • dry weight compound stocks were dissolved to a concentration of 1OmM in 100% DMSO.
  • Compounds were further diluted in 100% DMSO to generate a dose range of between 600 ⁇ M to 100 nM. 5 ⁇ L of compound dilution was then added to 95 ⁇ l of cells to give a final dose range of 30 ⁇ M to 5 nM compound in 0.3% DMSO. Plates were then incubated at 37 0 C in the presence of 5% CO 2 for a further 72 hours post-dosing. On day 5, lO ⁇ l Alamar Blue solution (Invitrogen) was added to each well and the plate returned to the incubator for a further 4 hours. Alamar Blue is an oxidation-reduction indicator dye, which monitors metabolic activity (high level of reduction) as a readout of cellular proliferation.
  • Cell viability was analysed using the Guava ® Viacount Assay.
  • Cells were routinely cultured in their appropriate growth media (according to ATCC cell biology collection guidelines) for between 5-10 passages prior to compound testing.
  • 10,000 cells were plated in the internal 60 wells of black 96 well plates (Costar).
  • HBSS Hanks Buffered salt solution
  • HBSS Hanks Buffered salt solution
  • dry weight compound stocks (compound A) were dissolved to a concentration of 1OmM in 100% DMSO.
  • Compounds were further diluted in 100% DMSO to generate a dose range of between 200 ⁇ M to 20 nM.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un nouveau procédé de traitement ou de prophylaxie du cancer, comprenant l'administration à un patient en ayant besoin d'une quantité thérapeutiquement efficace d'un composé inhibant le transport de monocarboxylate.
PCT/GB2010/050096 2009-02-06 2010-01-22 Utilisation d'un inhibiteur de mct1 de traitement du cancer exprimant mct1 sur mct4 Ceased WO2010089580A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15044909P 2009-02-06 2009-02-06
US61/150,449 2009-02-06

Publications (1)

Publication Number Publication Date
WO2010089580A1 true WO2010089580A1 (fr) 2010-08-12

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Application Number Title Priority Date Filing Date
PCT/GB2010/050096 Ceased WO2010089580A1 (fr) 2009-02-06 2010-01-22 Utilisation d'un inhibiteur de mct1 de traitement du cancer exprimant mct1 sur mct4

Country Status (1)

Country Link
WO (1) WO2010089580A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013112881A1 (fr) * 2012-01-27 2013-08-01 Thomas Jefferson University Procédés pronostique et thérapeutique liés à l'inhibiteur de la protéine mct
US9296728B2 (en) 2012-01-20 2016-03-29 Regents Of The University Of Minnesota Therapeutic compounds
WO2016063037A1 (fr) * 2014-10-20 2016-04-28 Queen Mary University Of London Inhibiteurs de transporteurs de lactate destinés à être utilisés dans le traitement de maladies inflammatoires
WO2016118823A1 (fr) 2015-01-22 2016-07-28 The Scripps Research Institute Inhibiteurs ptéridine dione du transporteur de monocarboxylate
WO2016118825A1 (fr) 2015-01-22 2016-07-28 The Scripps Research Institute Inhibiteurs hétérocycliques de transporteurs de monocarboxylate
CN107646035A (zh) * 2015-03-26 2018-01-30 拜耳制药股份公司 作为腺苷a2b受体拮抗剂的杂环基甲基噻吩并尿嘧啶
US10022372B2 (en) 2013-04-19 2018-07-17 Thomas Jefferson University Caveolin-1 related methods for treating glioblastoma with temozolomide
WO2019191599A1 (fr) * 2018-03-30 2019-10-03 Vincent Sandanayaka Carboxylates d'énone bicycliques utilisés en tant que modulateurs de transporteurs et leurs utilisations
WO2019215316A1 (fr) 2018-05-11 2019-11-14 Astrazeneca Ab Composés de triazolopyrimidine et leur utilisation dans le traitement du cancer
WO2021061929A1 (fr) * 2019-09-25 2021-04-01 Nirogy Therapeutics, Inc. Carboxylates bicycliques utilisés en tant que modulateurs de transporteurs et leurs utilisations
CN112888673A (zh) * 2018-04-25 2021-06-01 查尔斯德鲁医药科学大学 新颖mct4抑制剂及其用途
WO2024031445A1 (fr) * 2022-08-10 2024-02-15 Vettore, LLC Procédés et méthodes de préparation d'inhibiteurs de mct4

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9296728B2 (en) 2012-01-20 2016-03-29 Regents Of The University Of Minnesota Therapeutic compounds
US9573888B2 (en) 2012-01-20 2017-02-21 Regents Of The University Of Minnesota Therapeutic compounds
GB2523211A (en) * 2012-01-27 2015-08-19 Univ Jefferson MCT protein inhibitor-related prognostic and therapeutic methods
GB2523211B (en) * 2012-01-27 2020-03-18 Univ Jefferson MCT protein inhibitor-related prognostic and therapeutic methods
WO2013112881A1 (fr) * 2012-01-27 2013-08-01 Thomas Jefferson University Procédés pronostique et thérapeutique liés à l'inhibiteur de la protéine mct
US10085987B2 (en) 2012-01-27 2018-10-02 Thomas Jefferson University MCT protein inhibitor-related prognostic and therapeutic methods
US10022372B2 (en) 2013-04-19 2018-07-17 Thomas Jefferson University Caveolin-1 related methods for treating glioblastoma with temozolomide
WO2016063037A1 (fr) * 2014-10-20 2016-04-28 Queen Mary University Of London Inhibiteurs de transporteurs de lactate destinés à être utilisés dans le traitement de maladies inflammatoires
WO2016118825A1 (fr) 2015-01-22 2016-07-28 The Scripps Research Institute Inhibiteurs hétérocycliques de transporteurs de monocarboxylate
JP2018502876A (ja) * 2015-01-22 2018-02-01 ザ スクリプス リサーチ インスティテュート 複素環式のモノカルボン酸トランスポータ阻害薬
WO2016118823A1 (fr) 2015-01-22 2016-07-28 The Scripps Research Institute Inhibiteurs ptéridine dione du transporteur de monocarboxylate
US10851113B2 (en) 2015-01-22 2020-12-01 The Scripps Research Institute Heterocyclic inhibitors of monocarboxylate transporters
US11560389B2 (en) 2015-01-22 2023-01-24 University Of Florida Research Foundation, Incorporated Heterocyclic inhibitors of monocarboxylate transporters
CN107646035A (zh) * 2015-03-26 2018-01-30 拜耳制药股份公司 作为腺苷a2b受体拮抗剂的杂环基甲基噻吩并尿嘧啶
WO2019191599A1 (fr) * 2018-03-30 2019-10-03 Vincent Sandanayaka Carboxylates d'énone bicycliques utilisés en tant que modulateurs de transporteurs et leurs utilisations
CN112105356A (zh) * 2018-03-30 2020-12-18 尼罗根治疗有限公司 作为转运蛋白的调节剂的双环烯酮羧酸酯类化合物及其应用
CN112888673B (zh) * 2018-04-25 2022-07-29 查尔斯德鲁医药科学大学 新颖mct4抑制剂及其用途
CN112888673A (zh) * 2018-04-25 2021-06-01 查尔斯德鲁医药科学大学 新颖mct4抑制剂及其用途
WO2019215316A1 (fr) 2018-05-11 2019-11-14 Astrazeneca Ab Composés de triazolopyrimidine et leur utilisation dans le traitement du cancer
EP4134368A1 (fr) 2018-05-11 2023-02-15 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Composés de triazolopyrimidine et leur utilisation dans le traitement du cancer
CN114615980A (zh) * 2019-09-25 2022-06-10 尼罗根治疗有限公司 作为转运蛋白调节剂的双环羧酸酯及其用途
WO2021061929A1 (fr) * 2019-09-25 2021-04-01 Nirogy Therapeutics, Inc. Carboxylates bicycliques utilisés en tant que modulateurs de transporteurs et leurs utilisations
WO2024031445A1 (fr) * 2022-08-10 2024-02-15 Vettore, LLC Procédés et méthodes de préparation d'inhibiteurs de mct4

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