WO2017170981A1 - Agent prophylactique ou thérapeutique contre une maladie liée à fgfr3 - Google Patents

Agent prophylactique ou thérapeutique contre une maladie liée à fgfr3 Download PDF

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WO2017170981A1
WO2017170981A1 PCT/JP2017/013524 JP2017013524W WO2017170981A1 WO 2017170981 A1 WO2017170981 A1 WO 2017170981A1 JP 2017013524 W JP2017013524 W JP 2017013524W WO 2017170981 A1 WO2017170981 A1 WO 2017170981A1
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ggti
inhibitor
ips cells
fti
drug
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範行 妻木
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国立大学法人京都大学
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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

Definitions

  • the present invention relates to a preventive or therapeutic agent for fibroblast growth factor receptor 3 (FGFR3) disease.
  • FGFR3 fibroblast growth factor receptor 3
  • FGFR3 fibroblast growth factor receptor 3
  • Non-Patent Document 1 Jonquoy et al. By tyrosine kinase inhibitors (Non-Patent Document 1), Rauchenberger et al. By FGFR3 neutralizing antibody (Non-Patent Document 2), and Yasoda et al. By c-type natriuretic peptide (CNP) (Non-patent Document 1).
  • Patent Document 3 reports a method of inhibiting excessive signal transduction from FGFR3. Some of these methods actually restore bone growth in model mice with cartilage dysplasia associated with FGFR3.
  • the present inventors searched for therapeutic drug candidates using iPS cells prepared using somatic cells derived from patients with FGFR3 disease, and statins that are hyperlipidemic drugs are candidates for therapeutic drugs for FGFR3 disease. (Patent Literature 1 and Non-Patent Literature 4).
  • An object of the present invention is to provide a therapeutic and / or prophylactic agent for fibroblast growth factor receptor 3 (FGFR3) disease.
  • FGFR3 fibroblast growth factor receptor 3
  • the present inventor obtained metformin, a Farnesyl transferase inhibitor, It was found that Geranylgeranyl transferase inhibitor and Rock inhibitor promote differentiation induction from iPS cells derived from FGFR3 disease patients to chondrocytes.
  • metformin a Farnesyl transferase inhibitor
  • a pharmaceutical for treatment and / or prevention of FGFR3 disease comprising as an active ingredient at least one drug selected from the group consisting of a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor and a Rock inhibitor.
  • a drug selected from the group consisting of a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor and a Rock inhibitor.
  • the Farnesyl transferase inhibitor is Lonafarnib, Chaetomellic acid A, FPT Inhibitor I, FPT Inhibitor II, FPT Inhibitor III, FTase Inhibitor I, FTase Inhibitor II, FTI-276 trifluoroacetate salt, FTI-277 trifluoroacetate salt, L- 744,832
  • the medicament according to [1] which is a drug selected from the group consisting of Dihydrochloride, Manumycin A, Tipifarnnib, and ⁇ -hydroxy Farnesyl Phosphonic Acid.
  • the Geranylgeranyl transferase inhibitor is selected from the group consisting of GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297 and GGTI-298
  • the medicament according to [1] which is a medicinal agent.
  • the Rock inhibitor is a drug selected from the group consisting of Y-27632, Fasudil / HA1077, SR3677, GSK269962, H-1152 and Wf-536.
  • FGFR3 disease is lethal osteodysplasia (TD) and / or achondroplasia (ACH).
  • TD lethal osteodysplasia
  • ACH achondroplasia
  • a method for treating and / or preventing FGFR3 disease comprising administering at least one drug selected from the group consisting of metformin, a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor, and a Rock inhibitor. Including.
  • the Farnesyl transferase inhibitor is Lonafarnib, Chaetomellic acid A, FPT Inhibitor I, FPT Inhibitor II, FPT Inhibitor III, FTase Inhibitor I, FTase Inhibitor II, FTI-276 trifluoroacetate salt, FTI-277 trifluoroacetate salt, L- 744,832
  • the method according to [7] which is a drug selected from the group consisting of Dihydrochloride, Manumycin A, Tipifarnnib and ⁇ -hydroxy Farnesyl Phosphonic Acid.
  • the Geranylgeranyl transferase inhibitor is selected from the group consisting of GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297 and GGTI-298 [7] The method according to [7], wherein [11] The method according to [7], wherein the Rock inhibitor is an agent selected from the group consisting of Y-27632, Fasudil / HA1077, SR3677, GSK269962, H-1152 and Wf-536.
  • FGFR3 disease is lethal osteodysplasia (TD) and / or achondroplasia (ACH).
  • TD lethal osteodysplasia
  • ACH achondroplasia
  • [13] Use of at least one drug selected from the group consisting of metformin, a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor and a Rock inhibitor in the manufacture of a medicament for the treatment and / or prevention of FGFR3 disease.
  • the drug is metformin.
  • the Farnesyl transferase inhibitor is Lonafarnib, Chaetomellic acid A, FPT Inhibitor I, FPT Inhibitor II, FPT Inhibitor III, FTase Inhibitor I, FTase Inhibitor II, FTI-276 trifluoroacetate salt, FTI-277 trifluoroacetate salt, L- 744,832
  • the Geranylgeranyl transferase inhibitor is selected from the group consisting of GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297 and GGTI-298
  • the Rock inhibitor is a drug selected from the group consisting of Y-27632, Fasudil / HA1077, SR3677, GSK269962, H-1152 and Wf-536.
  • FGFR3 disease is lethal osteodysplasia (TD) and / or achondroplasia (ACH).
  • the Farnesyl transferase inhibitor is Lonafarnib, Chaetomellic acid A, FPT Inhibitor I, FPT Inhibitor II, FPT Inhibitor III, FTase Inhibitor I, FTase Inhibitor II, FTI-276 trifluoroacetate salt, FTI-277 trifluoroacetate salt, L- 744,832
  • the drug according to [19] which is a drug selected from the group consisting of Dihydrochloride, Manumycin A, Tipifarnnib and ⁇ -hydroxy Farnesyl Phosphonic Acid.
  • the Geranylgeranyl transferase is selected from the group consisting of GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297 and GGTI-298
  • the Rock inhibitor is a drug selected from the group consisting of Y-27632, Fasudil / HA1077, SR3677, GSK269962, H-1152 and Wf-536.
  • chondrocytes induced by differentiation from healthy individual-derived iPS cells and undifferentiated healthy individual-derived iPS cells (iPSC) are also shown.
  • Vehicle base
  • Rosuva Rosuvastatin
  • TD714 using a low cholesterol medium The results of Safranin O-fast green-iron hematoxylin staining of particles induced from iPS cells are shown.
  • TD714-derived iPS cells ACH8858-derived iPS cells, or healthy individual-derived iPS cells using a medium supplemented with vehicle (base), 1 ⁇ M Rosuvastatin (rosuvastatin) and metformin (Met) at each concentration (0.2 mM or 2 mM) 409B2) shows the results of Safranin O-fast green-iron hematoxylin staining of particles induced to differentiate into cartilage.
  • TD714-derived iPS cells TD714-derived iPS cells, ACH8858-derived iPS cells, or healthy individuals-derived iPS using a medium supplemented with vehicle (base), 1 ⁇ M Rosuvastatin (rosuvastatin) and metformin (Met) at each concentration (0.2 mM, 2 mM or 5 mM)
  • base 1 ⁇ M Rosuvastatin (rosuvastatin) and metformin (Met) at each concentration (0.2 mM, 2 mM or 5 mM)
  • grains which induced differentiation from the cell (409B2) to the cartilage by real-time PCR is shown.
  • FGFR3 disease refers to any bone morphogenetic disease in which bone dysplasia is caused by having a mutation in FGFR3.
  • FGFR3 disease preferably means a series of diseases belonging to the FGFR3 disease group described in the international classification of bone system diseases (Warman et al., Am J Med Genet 155A (5): 943-68 (2011)).
  • TD lethal osteodysplasia
  • ACH achondroplasia
  • CASHL hearing loss syndrome
  • Crouzon-like craniosynostosis with acanthosis nigricans Crouzonodermoskeletal
  • Examples include early skull fusion.
  • the mutation occurring in FGFR3 may be either a gain-of-function type mutation or a function-deficient type mutation, but may preferably be a gain-of-function type mutation.
  • the therapeutic and / or prophylactic agent for a disease having a mutation in FGFR is at least one selected from the group consisting of metformin, Farnesyl transferase inhibitor, Geranylgeranyl transferase inhibitor, and Rock inhibitor. It is a medicine containing a drug as an active ingredient.
  • the active ingredient may be at least one drug selected from the group consisting of metformin and a Farnesyl transferase inhibitor, and may be metformin.
  • Metformin (chemical name: 1,1-Dimethylbiguanide, CAS number: 657-24-9, C 4 H 11 N 5 ) is known as a biguanide hypoglycemic drug. Metformin hydrochloride is formulated and marketed.
  • the Farnesyl transferase inhibitor in the present invention is not particularly limited as long as it can suppress the function of Farnesyl transferase.
  • Lonafarnib (CAS number: 193275-84-2, C 27 H 31 Br 2 ClN 4 O 2 , for example, Shen M et al., Drug Discov Today 20, 267-276 (2015))
  • Chaetomellic acid A (CAS number: 148796-51-4, C 19 H 32 O 4 2Na, eg, JB Gibbs, et al .; J. Biol. Chem. 268, 7617 (1993), F. Tamanoi; Trends Biochem. Sci.
  • FPT Inhibitor I C 19 H 29 NO 6 P 3Na, eg, Manne, V. , et al. 1995. Drug Development Res. 34, 121, Patel, DV, et al. 1995. J. Med. Chem. 38, 2906
  • FPT Inhibitor II C 17 H 28 NO 5 P 2Na, eg, Manne, V., et al. 1995. Drug Development Res. 34, 121
  • FPT Inhibitor III C 23 H 39 NO 7 P Na, eg, Wang, D., et al. 1998. J. Biol. Chem) 273, 33027, Manne, V., et al. 1995. Drug Development Res.
  • FTase Inhibitor I (CAS number: 149759-96-6, C 22 H 38 N 4 O 3 S 2 , eg , Cox, A D., et al., 1994 The Journal of biological chemistry. 269 (30): 19203-6, Garcia, A M., et al., 1993 The Journal of biological chemistry. 268 (25): 18415-8 ), FTase Inhibitor II (CAS number: 156707-43-6, C 15 H 21 N 3 O 4 S 2 , eg, Song, Jia L., et al., 2003 Microbiology (Reading, England).
  • FTI-276 trifluoroacetate salt (CAS number: 170006-72-1 (free base), C 21 H 27 N 3 O 3 S 2 C 2 HF 3 O 2 , eg, Cohen-Jonathan, E., et al., 1999 Radiation research. 152 (4): 404-11), FTI-277 trifluoroacetate salt (CAS number: 170006-73-2 (free base), C 22 H 29 N 3 O 3 S 2 x C 2 HF 3 O 2 , eg, Cohen-Jonathan, E., et al., 1999 Radiation research.
  • Tipifarnib (CAS number: 192185-72-1, C 27 H 22 Cl 2 N 4 O, see eg Shen M et al., Drug Discov Today 20, 267-276 (2015)) and ⁇ -hydroxy Farnesyl Phosphonic Acid ( CAS number: 148796-53-6, C 15 H 27 O 4 P, for example, see Pompliano, DL, Rands, E., Schaber, MD, et al., Biochemistry 31 3800-3807 (1992)) It is not limited to these.
  • the Geranylgeranyl transferase inhibitor in the present invention is not particularly limited as long as it can suppress the function of Geranylgeranyl transferase.
  • GGTI-2418 (CAS number: 171744-11-9, C 23 H 31 N 3 O 3 S, for example) , Shen M et al, Drug Discov Today 20, see 267-276 (2015)
  • GGTI- 2133 (CAS number:. 191102-79-1, C 27 H 28 N 4 O 3 C 2 HF 3 O 2, example , Shen M et al., Drug Discov Today 20, 267-276 (2015))
  • GGTI-2147 CAS number: 191102-87-1, C 28 H 30 N 4 O 3 , eg, Bernot, D., et al. 2003.
  • GGTI-2154 (CAS number: 251577-10-3, eg, Shen M et al., Drug Discov Today 20, 267-276 (2015)).
  • GGTI-2166 (Nikkaji number: J1.244.741H, C 25 H 30 N 4 O 3 )
  • GGTI-286 (CAS number: 171744-11-9, C 23 H 31 N 3 O 3 S, for example)
  • GGTI-287 (C 22 H 29 N 3 O 3 S, eg, Shen M et al.
  • GGTI-297 (CAS Number:. 181045-83-0, C 26 H 31 N 3 O 3 S C 2 HF 3 O 2, example, Sun, J., et al 1998. Oncogene 16, 1467 reference) and GGTI-298 (CAS number: 180977-44-0, C 27 H 33 N 3 O 3 S CF 3 CO 2 H, eg, McGuire, T F., et al., 1996 The Journal of biological chemistry. 271 (44 ): 27402-7), but not limited to.
  • the Rock inhibitor in the present invention is not particularly limited as long as it can suppress the function of Rho-kinase (ROCK).
  • ROCK Rho-kinase
  • Y-27632 eg, Ishizaki et al., Mol. Pharmacol. 57, 976-983 (2000); Narumiya et al., Methods Enzymol. 325,273-284 (2000)
  • Fasudil / HA1077 eg, Uenata et al., Nature 389: 990-994 (1997)
  • SR3677 eg, Feng Y et al., J Med Chem. 51: 6642-6645 (2008)
  • GSK269962 eg, StavengerStRA et al., J Med Chem.
  • H- 1152 eg, Sasaki et al., Pharmacol. Ther. 93: 225-232 (2002)
  • Wf-536 eg Nakajima et al., Cancer Chemother Pharmacol. 52 (4): 319-324 (2003)
  • antisense nucleic acids to ROCK eg, siRNA
  • RNA interference inducing nucleic acids eg, siRNA
  • dominant negative mutants eg, and their expression vectors.
  • Other known low-molecular compounds can also be used as ROCK inhibitors (for example, US Patent Application Publication Nos. 2005/0209261, 2005/0192304, 2004/0014755, 2004/0002508).
  • ROCK inhibitors may be used.
  • metformin, Farnesyl transferase inhibitor, Geranylgeranyl transferase inhibitor or Rock inhibitor of the present invention includes pharmacologically acceptable salts thereof (preferably hydrochloride, sodium salt or calcium salt).
  • compositions for oral administration include solid or liquid dosage forms, specifically tablets (including dragees and film-coated tablets), pills, granules, powders, capsules (including soft capsules). Syrup, emulsion, suspension and the like.
  • compositions for parenteral administration for example, injections, suppositories and the like are used, and injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like.
  • Dosage forms may be included. These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate and magnesium metasilicate aluminate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate), lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; Colloidal silica; like bead wax, gay wax Boric acid; adipic acid; sulfate such as sodium sul
  • the dose of the drug of the present invention to a patient varies depending on the type of pathological condition to be treated, symptoms and severity of the disease, patient age, sex or body weight, administration method, etc. By determining in consideration of the above situation, an appropriate dose can be determined as appropriate.
  • the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 1000 mg (preferably 500 mg).
  • the lower limit is 0.01 mg (preferably 0.05 mg) and an upper limit of 100 mg (preferably 50 mg) can be administered to adults 1 to 6 times per day. The dose may be increased or decreased depending on the symptoms.
  • Example 1 Generation of iPS cells All the following experiments were conducted with the approval of the clinical trial review committee, animal experiment committee and institutional biosafety committee, and Kyoto University.
  • HDF human dermal fibroblasts derived from TD patients (TD714, TD10749, TD315H and TD329N) were obtained from the Coryell Medical Research Institute and Saitama Children's Medical Center. Sequence analysis of genomic DNA extracted from these human dermal fibroblasts (HDF) confirmed a heterozygous mutation (Arg248Cys) in the FGFR3 gene in all TD patients. As HDFs from ACH patients, HDFs (ACH8857 and ACH8858) of two ACH patients with a Gly380Arg heterozygous mutation in the FGFR3 gene, and HDF (ACHhomo-8859) showing more severe chondrogenesis than ACH Obtained from the Coryell Medical Institute.
  • IPS cells were prepared from the HDF derived from each patient by the method described below.
  • As control iPS cells a healthy individual-derived iPS cell line (409B2) obtained from K. Okita and S. Yamanaka (Kyoto University iPS Cell Laboratory) (Okita, K., et al. Nature methods 8, 409-412 (2011)).
  • iPS cells were produced by the following method. Specifically, each obtained human fibroblast (HDF) was cultured in DMEM (Sigma) supplemented with 10% FBS (Invitrogen), 50 U / ml penicillin and 50 ⁇ g / ml streptomycin. Subsequently, episomal plasmid vectors (Mixture Y4: OCT3 / 4, SOX2, KLF4, L-MYC, LIN28 and p53 shRNA) were electroporated into each HDF by Neon transfection system (Invitrogen) (Okita, K ., et al. Nature methods 8, 409-412 (2011)).
  • Neon transfection system Invitrogen
  • Example 2 Differentiation from each iPS cell was induced to chondrocytes according to the method described below, which was modified from a method reported before cartilage induction (Oldershaw, RA, et al., Nat Biotechnol 28, 1187-1194 (2010)).
  • Each iPS cell was seeded on a Matrigel (Invitrogen) coated dish, a medium supplemented with 50 units / ml penicillin and 50 ⁇ g / ml streptomycin was added to Essential 8 medium (Life Technologies), and cultured under feeder-free conditions.
  • colonies consisting of 1-2 ⁇ 10 5 cells were transformed into mesodermal differentiation medium (10 ng / ml Wnt3A (R & D), 10 ng / ml activin A (R & D), 1% insulin for DMEM / F12) -Transferrin-sodium selenite (Invitrogen), 1% fetal bovine serum, 50 units / ml penicillin, 50 ⁇ g / ml prepared by mixing streptomycin) (Day 0 of differentiation induction).
  • mesodermal differentiation medium (10 ng / ml Wnt3A (R & D), 10 ng / ml activin A (R & D), 1% insulin for DMEM / F12) -Transferrin-sodium selenite (Invitrogen), 1% fetal bovine serum, 50 units / ml penicillin, 50 ⁇ g / ml prepared by mixing streptomycin) (Day 0 of differentiation induction).
  • each drug (1 ⁇ M rosuvastatin (BioVision, 1995-5), each concentration (0.1 ⁇ M, 1 ⁇ M or 10 ⁇ M) of Farnesyl transferase inhibitor (FTI-277) (Sigma) (hereinafter, FTI), Geranylgeranyl transferase inhibitor (GGTI-287) (Sigma) (hereinafter referred to as GGTI) at each concentration (0.1 ⁇ M, 1 ⁇ M or 10 ⁇ M), Rock inhibitor at each concentration (0.1 ⁇ M, 1 ⁇ M, 10 ⁇ M or 100 ⁇ M) (Y27632) (Wako) (hereinafter referred to as Rocki)) cartilage differentiation medium (50 ⁇ g / ml ascorbic acid, 10 ng / ml BMP2 (Osteopharma), 10 ng / ml TGF ⁇ (Pepro Tech), 10 ng / ml GDF5, 1% Insulin-transferrin-sodium
  • FTI-277 Sigma
  • Lonafarnib Lona
  • Tipifarnib LCL
  • the culture medium was replaced with a cartilage differentiation medium added at 0.01 ⁇ M or 0.1 ⁇ M, the cells were peeled off from the dish on the 14th day of induction of differentiation, and cultured for 28 days in suspension culture using the same medium. It was collected.
  • the expression level of mRNA of the genes encoding chondrocyte marker SOX9 and cartilage matrix protein (type II collagen (COL2A1) and aggrecan (Acan)) was examined by real-time PCR.
  • the obtained particles were stained with safranin O to confirm the presence of safranin O-positive cartilage tissue and to determine the ratio of safranin O-positive regions.
  • Fig. 1 shows a medium containing TD714-derived iPS cells supplemented with Farnesyl transferase inhibitor (FTI-277), Geranylgeranyl transferase inhibitor (GGTI-287), or Rock inhibitor (Y27632).
  • FTI-277 Farnesyl transferase inhibitor
  • GGTI-287 Geranylgeranyl transferase inhibitor
  • Rock inhibitor Y27632
  • Fig. 5 shows the results of real-time PCR measurement of chondrocyte markers in chondrocytes induced by differentiation from TD714-derived iPS cells using media supplemented with three types of Farnesyl transferase inhibitors (FTI-277, Lonafarnib and Tipifarnib). Indicated. (A) is the result of SOX9, (B) is the result of COL2A1, and (C) is the result of Acan. Even when any Farnesyl transferase inhibitor was used, it was confirmed that the expression of each gene was increased as compared with Vehicle (base).
  • FTI-277 Farnesyl transferase inhibitors
  • FIG. 6 and FIG. 7 show the results of staining with Safranin O for particles induced to differentiate from TD714-derived iPS cells using media supplemented with three types of Farnesyl transferase inhibitors (FTI-277, Lonafarnib and Tipifarnib), respectively. . Safranin O-positive cartilage tissue was confirmed when any Farnesyl transferase inhibitor was used.
  • FTI-277 Farnesyl transferase inhibitors
  • Fig. 10 shows the results of real-time PCR measurement of chondrocyte markers in chondrocytes induced to differentiate from TD329N-derived iPS cells using media supplemented with three types of Farnesyl transferase inhibitors (FTI-277, Lonafarnib and Tipifarnib). Indicated. (A) is the result of SOX9, (B) is the result of COL2A1, and (C) is the result of Acan. Even when any Farnesyl transferase inhibitor was used, it was confirmed that the expression of each gene was increased as compared with Vehicle (base).
  • FTI-277 Farnesyl transferase inhibitors
  • FIG. 11 and FIG. 12 show the addition of Farnesyl transferase inhibitor (FTI-277), Geranylgeranyl transferase inhibitor (GGTI-287), or Rock inhibitor (Y27632) from ACH8858-derived iPS cells.
  • FTI-277 Farnesyl transferase inhibitor
  • GGTI-287 Geranylgeranyl transferase inhibitor
  • Rock inhibitor Y27632
  • FIG. 13 shows the results of real-time PCR measurement of chondrocyte markers in chondrocytes induced to differentiate from ACH8858-derived iPS cells using media supplemented with three types of Farnesyl transferase inhibitors (FTI-277, Lonafarnib and Tipifarnib), respectively. Indicated. (A) is the result of SOX9, (B) is the result of COL2A1, and (C) is the result of Acan. Even when any Farnesyl transferase inhibitor was used, it was confirmed that the expression of each gene was increased as compared with Vehicle (base).
  • FTI-277 Farnesyl transferase inhibitors
  • FIG. 14 and FIG. 15 show that from ACHhomo-8859-derived iPS cells, a Farnesyl transferase inhibitor (FTI-277), Geranylgeranyl transferase inhibitor (GGTI-287), or Rock inhibitor. (Y27632) The results of staining with Safranin O for the particles induced to differentiate using the added medium are shown. Safranin O-positive cartilage tissue was confirmed when any drug was used.
  • FIG. 16 shows real-time PCR for chondrocyte markers in chondrocytes induced to differentiate from ACHhomo-8859-derived iPS cells using media supplemented with three types of Farnesyl transferase inhibitors (FTI-277, Lonafarnib and Tipifarnib). Results are shown.
  • FTI-277 Farnesyl transferase inhibitors
  • B is the result of COL2A1
  • C is the result of Acan. Even when any Farnesyl transferase inhibitor was used, it was confirmed that the expression of each gene was increased as compared with Vehicle (base).
  • Example 3 Except for changing the test drug to metformin, chondrocytes were induced from TD714-derived iPS cells and ACH8858-derived iPS cells in the same manner as in Example 2. As a control iPS cell, 409B2 derived from a healthy individual was used. The concentration of metformin (1,1-Dimethylbiguanide hydrochloride (sigma)) was 0.2 mM, 2 mM or 5 mM.
  • FIG. 17 shows the result of Safranin O staining of particles induced to differentiate using a medium supplemented with metformin. Safranin O-positive cartilage tissue was confirmed in both particles induced to differentiate from TD714-derived iPS cells and ACH8858-derived iPS cells.
  • FIG. 18 shows the results of real-time PCR measurement of chondrocyte markers (COL2A1, Acan, SOX9) in chondrocytes induced to differentiate using a medium supplemented with metformin.
  • the expression level of each gene was expressed as a relative value, assuming that the expression level when TD714-derived iPS cells were induced to differentiate with 1 ⁇ M rosuvastatin was 1. It was confirmed that the addition of metformin increases the expression of each gene.
  • metformin By using metformin, Farnesyl transferase inhibitor, Geranylgeranyl transferase inhibitor or Rock inhibitor, cartilage tissue can be formed even from iPS cells derived from TD patients and iPS cells derived from ACH patients It was confirmed that it was possible. Therefore, it was suggested that metformin, Farnesyl® transferase inhibitor, Geranylgeranyl® transferase inhibitor and Rock inhibitor can be therapeutic agents for lethal osteodysplasia and achondroplasia.
  • the present invention provides a substance that promotes differentiation into chondrocytes obtained as a result of screening, and the substance can be used as a new therapeutic agent and / or preventive agent for FGFR3 disease.

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Abstract

La présente invention concerne un agent thérapeutique et/ou prophylactique contre une maladie liée à FGFR3, qui contient au moins une substance chimique choisie dans le groupe constitué par la metformine, un inhibiteur de farnésyl transférase, un inhibiteur de géranylgéranyl transférase et un inhibiteur de Rock en tant que principe actif.
PCT/JP2017/013524 2016-04-01 2017-03-31 Agent prophylactique ou thérapeutique contre une maladie liée à fgfr3 WO2017170981A1 (fr)

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WO2019093389A1 (fr) * 2017-11-08 2019-05-16 公益財団法人 東京都医学総合研究所 Agent thérapeutique pour le retard mental ou l'autisme
JP2020115771A (ja) * 2019-01-22 2020-08-06 国立大学法人京都大学 多能性幹細胞から軟骨組織を製造する方法
WO2024061474A1 (fr) * 2022-09-23 2024-03-28 Norwegian University Of Science And Technology (Ntnu) Polythérapie pour le traitement ou la prévention de troubles neurologiques

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WO2004091660A1 (fr) * 2003-04-17 2004-10-28 Kowa Co., Ltd. Promoteur de l'expression du gene lklf/klf2
JP2009513660A (ja) * 2005-10-26 2009-04-02 旭化成ファーマ株式会社 肺動脈性高血圧の治療用併用療法におけるファスジル
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WO2004091660A1 (fr) * 2003-04-17 2004-10-28 Kowa Co., Ltd. Promoteur de l'expression du gene lklf/klf2
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019093389A1 (fr) * 2017-11-08 2019-05-16 公益財団法人 東京都医学総合研究所 Agent thérapeutique pour le retard mental ou l'autisme
JPWO2019093389A1 (ja) * 2017-11-08 2020-11-19 公益財団法人東京都医学総合研究所 知的障害又は自閉症治療薬
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JP7269620B2 (ja) 2019-01-22 2023-05-09 国立大学法人京都大学 多能性幹細胞から軟骨組織を製造する方法
WO2024061474A1 (fr) * 2022-09-23 2024-03-28 Norwegian University Of Science And Technology (Ntnu) Polythérapie pour le traitement ou la prévention de troubles neurologiques

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