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WO2013037482A1 - Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer - Google Patents

Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer Download PDF

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Publication number
WO2013037482A1
WO2013037482A1 PCT/EP2012/003814 EP2012003814W WO2013037482A1 WO 2013037482 A1 WO2013037482 A1 WO 2013037482A1 EP 2012003814 W EP2012003814 W EP 2012003814W WO 2013037482 A1 WO2013037482 A1 WO 2013037482A1
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Prior art keywords
fxr
cyclopropyl
fxr agonist
agonist
expression
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Ceased
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PCT/EP2012/003814
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English (en)
Inventor
Ulrich Deuschle
Claus Kremoser
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Phenex Pharmaceuticals AG
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Phenex Pharmaceuticals AG
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Publication of WO2013037482A1 publication Critical patent/WO2013037482A1/fr
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    • 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
    • A61K31/42—Oxazoles
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the Farnesoid X Receptor (FXR, NR1H4) is a member of the nuclear hormone receptor superfamily, predominantly expressed in tissues exposed to high levels of bile acids, such as the entire gastrointestinal tract, the liver and the gallbladder. FXR mRNA can also be detected in tissues such as the adrenals, kidneys and adipose tissues (B. Goodwin et al., Mol. Cell 2000, 6, 517). FXR senses bile acids as endogenous ligands (D. J. Parks et al., Science 1999, 284, 1365), is a master regulator of bile acid homeostasis and prevents bile acid-induced liver toxicity by regulating directly and indirectly (e.g.
  • FXR farnesoid X receptor
  • Activation of FXR results in hepatoprotection in mouse models of non alcoholic fatty liver disease possibly mediated via a reduction of lipid accumulation, fibrosis and inflammation (S. Fiorucci et al., J. Pharmacol. Exp. Ther. 2005, 314, 584; S. Zhang et al., J. Hepatol. 2009, 51 , 380).
  • FXR controls the expression of FGF15 in the mouse and FGF19 in humans.
  • FGF19 injected into mice results in insulin sensitization, body weight and lipid lowering.
  • N-myc downregulated gene 2 (human gene NDRG2, mouse gene Ndrg2) was reported as a candidate tumor suppressor in human liver cancer metastasis (D. C. Lee et al., Cancer Res. 2008, 68, 4210). Furthermore, reduced NDRG2 expression was published for high-risk adenomas and colorectal carcinoma (A. Lorentzen et al., BMC Cancer 2007, 7, 192; Y. J. Kim et al., Carcinogenesis 2009, 30, 598; A. Piepoli et al., BMC Med. Genomics 2009, 2, 1 1 ; D. Chu et al., Mol. Cancer Ther. 201 1 , 10, 47), glioblastoma (M.
  • the RECK gene has been implicated in the suppression of malignancies through inhibition of matrix metalloproteases (MMPs). No anti-tumor effect in vivo was shown in the two above listed patent applications.
  • MMPs matrix metalloproteases
  • the expression of RECK is only found to be reduced in stage 1 but not in other stages of HCC, suggesting that RECK may play a role in early (stage 1) hepatocarcinogenesis but not in later stages (see Fig. 9 of EXAMPLE 9).
  • NDRG2 expression was found reduced in all HCC stages compatible with an important role of NDRG2 in hepatocarcinognesis of all stages.
  • the problem underlying the present invention is the provision of FXR agonists for use in the treatment or prevention of cancers, metastases, precancerogenic lesions or angiogenesis in the context of cancer in a patient. Said problem has been solved by FXR agonists which induce the expression of NDRG2 in a patient.
  • the invention is further based on the unexpected finding that agonists of FXR can reduce the growth rate and metastasis of SK- Hep-1 cells (human hepatocellular carcinoma cells) orthotopically transplanted into the livers of immunodeficient nude mice. Further the invention is based on the unexpected finding that agonists of FXR can even more efficiently reduce the growth rate and metastasis of SK-GI-18 cells (SK-Hep-1 derivative that contains a stably integrated FXR cDNA under control of the human CMV IE promoter and stably expresses human FXR (isoform 3 accession Nr. NM_005123)) when orthotopically transplanted into the livers of immunodeficient nude mice (see EXAMPLE 10).
  • At least one FXR agonist for use in increasing NDRG2 gene expression in a cell is provided, wherein the at least one FXR agonist is administered to a cell in an effective amount.
  • FXR agonist induces expression of the NDRG2 gene in the cell.
  • FXR is known to bind to IR-1 type Sequences within genes regulated by FXR.
  • IR-1 type elements are identified in the first introns of the NDRG2 genes of humans, mouse and rat (FIG. 2).
  • FIG. 2 When cloned into pGL4 (Promega), the human IR1 sequence was found to be functional in luciferase reporter gene assays in vitro (FIG. 2).
  • a mutated version of the NDRG2 IR-1 type element (FIG. 1) has lost functionality in this assay (FIG. 2).
  • NDRG2 mRNA was upregulated by the non-steroidal FXR agonist Px20350 in a dose dependent fashion in HepG2 cells (FIG. 5A). This upregulation was pronounced when stably expressing human FXR in the stable HepG2 derivative HepG2-FXR5 (FIG. 5A). In HepG2-FXR5 cells, NDRG2 mRNA was also upregulated by the synthetic steroidal FXR agonist 6-ECDCA and with a lower potency by the natural bile acid CDCA (FIG. 5B potencies are: Px20350 EC50 66 nM, 6-EDCA 280 nM CDCA 33 ⁇ ). An upregulation of SHP mRNA was detected with non-steroidal and steroidal FXR agonists in both cell lines as well.
  • SK-Hep-1 cells are hepatoma cells, that do express rather low levels of FXR.
  • a stable SK- Hep-1 derivative (named SK-GI-18) was generated by stably transfecting a human FXR cDNA under control of a CMV promoter. While the levels of NDRG2 and the induction of NDRG2 by Px20350 was rather low in SK-Hep-1 cells, in SK-GI-18 cells, the relative levels of NDRG2 mRNA was increased (when normalized to TATA box binding protein mRNA) and the induciblity of NDRG2 mRNA by Px20350was increased (FIG. 6).
  • SK-Hep-1 cells do not change growth rate in vitro in response to the FXR agonist Px20350, SK-GI-18 cells that overexpress FXR do decrease their in vitro growth rate in a dose dependent fashion (FIG. 7).
  • RECK is described as a FXR modulated gene linked to a possible anti-malignant activity of FXR modulators.
  • the finding that RECK expression is not reduced in the more severe hepatocellular carcinoma stages II, IIIA and IV suggests that RECK could play only a significant role in very early stages of hepatocellular carcinoma. This is in contrast to NDRG2 and SHP, which are reduced in all HCC stages in a stage-dependent fashion (FIG. 9).
  • Exemplary tumors include but are not limited to hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer, and lung cancer.
  • the term "agonist" refers to an agent that triggers a response that is at least one response triggered by binding of an endogenous ligand of the receptor to the receptor.
  • the agonist may act directly or indirectly on a second agent that itself modulates the activity of the receptor.
  • the agonist may act indirectly by modulating the activity of one or more agent(s) that modulate the amount of FXR mRNA or FXR protein in certain cells of a patient.
  • the at least one response of the receptor is an activity of the receptor that can be measured with assays including but not limited to physiological, pharmacological, and biochemical assays.
  • agent refers to a substance including, but not limited to a chemical compound, such as a small molecule or a complex organic compound, a protein, such as an antibody or antibody fragment or a protein comprising an antibody fragment, or a genetic construct which acts at the DNA or mRNA level in an organism.
  • metalstatic refers to the process by which a cell, a group of cells, or a malignancy spreads from a site to sites not adjacent to the first site.
  • the FXR agonist is selected from a compound according to Formula (1 ), an enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutical acceptable salt thereof
  • a therapeutically effective dosage should produce a serum concentration of active agent of from about 0.1 ng/mL to about 50-100 g/mL
  • the pharmaceutical compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of FXR agonist per kilogram of body weight per day.
  • Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg, such as from about 10 to about 500 mg of the active agent or a combination of agents per dosage unit form.
  • compositions are intended to be administered by a suitable route, including by way of example and without limitation orally, parenterally, rectally, topically and locally.
  • a suitable route including by way of example and without limitation orally, parenterally, rectally, topically and locally.
  • capsules and tablets can be used for oral administration.
  • the compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components, in any combination: a sterile diluent, including by way of example without limitation, water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent including by way of example without limitation, water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent
  • antimicrobial agents such as benzyl alcohol and methyl parab
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the agent in the selected carrier or vehicle.
  • the effective concentration is sufficient for treating one or more symptoms of at least one malignancy and may be empirically determined.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, such as, by way of example and without limitation, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, such as, by way of example and without limitation, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, such as, by way of example and without limitation, acetate, sodium citrate, cyclodextr
  • Oral pharmaceutical dosage forms include, by way of example and without limitation, solid, gel and liquid.
  • Solid dosage forms include tablets, capsules, granules, and bulk powders.
  • Oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated.
  • Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
  • Disintegrating agents include, by way of example and without limitation, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • Coloring agents include, by way of example and without limitation, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • Sweetening agents include, by way of example and without limitation, sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors.
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the agents can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
  • a syrup may contain, in addition to the active agents, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
  • Solvents include by way of example and without limitation, glycerin, sorbitol, ethyl alcohol and syrup.
  • preservatives include without limitation glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Non-aqueous liquids utilized in emulsions include by way of example and without limitation, mineral oil and cottonseed oil.
  • Emulsifying agents include by way of example and without limitation, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • Sources of carbon dioxide include, by way of example and without limitation, sodium bicarbonate and sodium carbonate.
  • Coloring agents include, by way of example and without limitation, any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • Flavoring agents include, by way of example and without limitation, natural flavors extracted from plants such fruits, and synthetic blends of agents which produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule.
  • a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in US 4328245, 4409239, and 4410545.
  • the solution e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.
  • a pharmaceutically acceptable liquid carrier e.g., water
  • Tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
  • Parenteral administration generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients include by way of example and without limitation, water, saline, dextrose, glycerol or ethanol.
  • compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • the unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. Preparations for parenteral administration should be sterile, as is known and practiced in the art.
  • Assays that do not require washing or liquid separation steps can be used for high throughput screening systems and include biochemical assays such as fluorescence polarization assays (see e.g. J. C. Owicki, J. Biomol. Screen. 2000, 5, 297) scintillation proximity assays (SPA) (see e.g. J. W. Carpenter et al., Methods Mol. Biol. 2002, 190, 31) and fluorescence resonance energy transfer energy transfer (FRET) or time resolved FRET based coactivator recruitment assays (R. Mukherjee et al., J. Steroid Biochem. Mol. Biol. 2002, 81 , 217; G. Zhou et al., Mol. Endocrinol. 1998, 12, 1594).
  • biochemical assays such as fluorescence polarization assays (see e.g. J. C. Owicki, J. Biomol. Screen. 2000, 5, 297) scintillation proximity assays (SPA)
  • Reporter plasmids may be constructed using standard molecular biological techniques by placing cDNA encoding for the reporter gene downstream from a suitable minimal promoter.
  • luciferase reporter plasmids may be constructed by placing cDNA encoding firefly luciferase immediately down stream from the herpes virus thymidine kinase promoter (located at nucleotides residues -105 to +51 of the thymidine kinase nucleotide sequence) which is linked in turn to the various response elements.
  • a third cell based assay of utility for screening agents is a mammalian two-hybrid assay that measures the ability of the nuclear hormone receptor to interact with a cofactor in the presence of a ligand (see e.g. US 5667973, US 5283173 and US 5468614).
  • the basic approach is to create three plasmid constructs that enable the interaction of FXR with the interacting protein to be coupled to a transcriptional readout within a living cell.
  • the first construct is an expression plasmid for expressing a fusion protein comprising the interacting protein, or a portion of that protein containing the interacting domain, fused to a GAL4 DNA binding domain.
  • NDRG2 inhibits the secretion and activities of multiple MMPs.
  • the MMP may be MMP-9.
  • the amount of MMPs secreted from a cell treated in the absence or presence of a agent can be measured using standard assays including but not limited to Western blot, enzyme linked immunosorbent assay, and gelatin zymography. Agonists of FXR may induce the expression of NDRG2, thereby leading to decreased secretion of MMPs.
  • Cells that express FXR endogenously include, by way of example and without limitation: hepatocytes, including primary hepatocytes isolated from human, monkey, mouse, or rat, or hepatocyte cell lines, including HepG2, Huh7, or SK-Hep-1 cells; and intestinal cells including HT-29, CaCo2 and FHs 74 Int.
  • hepatocytes including primary hepatocytes isolated from human, monkey, mouse, or rat, or hepatocyte cell lines, including HepG2, Huh7, or SK-Hep-1 cells
  • intestinal cells including HT-29, CaCo2 and FHs 74 Int.
  • stage I cancers are often localized and are usually curable.
  • Stage II and IIIA cancers are usually more advanced and may have invaded the surrounding tissues and spread to lymph nodes.
  • Stage IV cancers include metastatic cancers that have spread to sites outside of lymph nodes.
  • NDRG2 expression has been shown to correlate with beneficial prognoses for several malignancies including hepatocellular carcinoma, colorectal cancer, and breast cancer.
  • Restoration of NDRG2 expression in malignant cells can suppress their invasive, metastatic, and angiogenic activities through inhibition of matrix metalloproteases.
  • NDRG2 expression in tumor cells has been shown to suppress MMP-2 and CD24 expression.
  • Methods of inducing NDRG2 expression are provided herein through administering at least one FXR agonist.
  • the FXR agonist, or pharmaceutically acceptable derivative thereof, is administered simultaneously with, prior to, or after administration of one or more of the above agents.
  • FIG. 8 shows the migration of SK-GI-18 and SK-Hep-1 cells in presence of DMSO or 1 ⁇ Px20350 in the growth medium.
  • FXR NR1 H4
  • NDRG2 NDRG2
  • SHP NR0B2
  • RECK mRNA levels were quantified in 8 normal, 34 HCC and 12 non-HCC liver disease (LD) cDNA ' s purchased from ORIGENE (Cat. Nr. LVRT501 ) by q-RT-PCR.
  • the cDNA samples have been obtained from patient liver samples verified by pathologists prior to isolation of RNA and conversion to cDNA which were normalized against beta-actin by RT-PCR and arrayed onto 96 well plate.
  • FIG. 9 Decreased expression of FXR and FXR target genes in human HCC.
  • a total of 34 HCC cDNA samples from different stages (7 samples stage I, 8 samples of stages II and 111 A, 12 non-HCC liver disease (LD) and 8 normal liver samples were studied.
  • the mRNA expression for the indicated genes (FXR (NR1 H4), NDRG2, SHP (NR0B2) and RECK) was determined by Real Time PCR on an ABI HT 7900 Real Time PCR device and the data are expressed as mean+SEM.
  • SK-Hep-1 cells and SK-GI-18 cells were grown in RPMI medium (Sigma) supplemented with 8.6% FCS (Sigma) and 20 mM Alanyl-Glutamine (Sigma).
  • NMRI female nude mice (Charles River, Sulzfeld, Germany) were implanted with 5x106 cell (either SK-Hep-1 or SK-GI-18) by injection into one liver lobe at experimental day 0 (Experiments done at Oncotest GmbH, Freiburg, Germany according to Oncotest SOP).
  • Sorafenib does reduce primary tumor formation and metastasis of tumor cells in mice receiving SK-Hep-1 or SK-GI-18 cells comparably well.
  • the FXR agonists Px20606 and also Px21256 do reduce the tumor growth and metastasis more effectively in SK-GI-18 cells that do stably express human FXR isoform 3 compared to SK-Hep-1 cells that do express only very low to undetectable levels of endogenous FXR.

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Abstract

La présente invention concerne un agoniste du récepteur du farnésoïde X (FXR) destiné à être utilisé dans le traitement ou la prévention de certains cancers, de certaines métastases, de certaines lésions pré-cancéreuses ou de l'angiogenèse dans le contexte d'un cancer chez un patient, l'agoniste du récepteur du farnésoïde X (FXR) étant administré en une quantité thérapeutiquement efficace au patient. La présente invention concerne en outre un agoniste du FXR destiné à être utilisé pour induire l'expression du gène NDRG2 dans certains tissus d'un patient, l'agoniste de FXR étant administré en une quantité thérapeutiquement efficace au patient. La présente invention concerne en outre un agoniste de FXR destiné à être utilisé pour réduire le taux de prolifération, la migration, la métastase ou l'angiogenèse de certaines tumeurs.
PCT/EP2012/003814 2011-09-15 2012-09-11 Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer Ceased WO2013037482A1 (fr)

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US201161535061P 2011-09-15 2011-09-15
US61/535,061 2011-09-15
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Cited By (43)

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CN106995416A (zh) * 2016-01-26 2017-08-01 上海翰森生物医药科技有限公司 Fxr激动剂及其制备方法和应用
WO2017128896A1 (fr) * 2016-01-26 2017-08-03 江苏豪森药业集团有限公司 Agoniste de fxr et son procédé de préparation et utilisation associée
WO2017147047A1 (fr) * 2016-02-22 2017-08-31 Alios Biopharma, Inc. Modulateurs de fxr et leurs procédés d'utilisation
WO2017180577A1 (fr) * 2016-04-13 2017-10-19 Intercept Pharmaceuticals, Inc. Procédés de traitement du cancer
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