JPWO2017170981A1 - Preventive or therapeutic agent for FGFR3 disease - Google Patents
Preventive or therapeutic agent for FGFR3 disease Download PDFInfo
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- JPWO2017170981A1 JPWO2017170981A1 JP2018509644A JP2018509644A JPWO2017170981A1 JP WO2017170981 A1 JPWO2017170981 A1 JP WO2017170981A1 JP 2018509644 A JP2018509644 A JP 2018509644A JP 2018509644 A JP2018509644 A JP 2018509644A JP WO2017170981 A1 JPWO2017170981 A1 JP WO2017170981A1
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- ggti
- inhibitor
- ips cells
- fti
- drug
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
Classifications
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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, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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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
- A61K31/21—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
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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
- A61K31/435—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
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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
- A61K31/435—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
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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
- A61K31/435—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
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- 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
Abstract
本発明は、有効成分としてメトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤から成る群より選択される少なくとも1つの薬剤を含む、FGFR3病の治療および/または予防用医薬を提供する。The present invention provides a medicament for the treatment and / or prevention of FGFR3 disease comprising, as an active ingredient, at least one drug selected from the group consisting of metformin, a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor, and a Rock inhibitor.
Description
本発明は、線維芽細胞増殖因子受容体3(FGFR3)病の予防または治療剤に関する。 The present invention relates to a preventive or therapeutic agent for fibroblast growth factor receptor 3 (FGFR3) disease.
致死性骨異形成症 (TD)や軟骨無形成症 (ACH)などの骨形成異常に関する疾患は、一般に線維芽細胞増殖因子受容体3(FGFR3)病と呼ばれており、FGFR3中の機能獲得型突然変異により引き起こされる疾患であると考えられている。したがって、これらの疾患の治療を行う上での分子標的として、FGFR3およびその下流のシグナル伝達経路に係る種々の分子が注目されており、FGFR3からの過剰なシグナル伝達を阻害する様々な方法が試みられてきた。 Diseases related to bone dysplasia such as lethal osteodysplasia (TD) and achondroplasia (ACH) are commonly called fibroblast growth factor receptor 3 (FGFR3) disease, and gain function in FGFR3. It is considered a disease caused by type mutations. Therefore, various molecules related to FGFR3 and its downstream signal transduction pathway are attracting attention as molecular targets for the treatment of these diseases, and various methods for inhibiting excessive signal transduction from FGFR3 have been tried. Has been.
例えば、Jonquoyらは、チロシンキナーゼ阻害剤(非特許文献1)により、Rauchenbergerらは、FGFR3の中和抗体(非特許文献2)により、およびYasodaらは、c型ナトリウム利尿ペプチド(CNP)(非特許文献3)により、FGFR3からの過剰なシグナル伝達を阻害する方法を報告している。これらの方法のうちいくつかは、実際に、FGFR3に関連する軟骨異形成のモデルマウスにおける骨成長を回復させている。しかしながら、変異型FGFR3を導入した形質転換細胞での確認に留まり、適切なヒト細胞モデルを用いての有効性は確認されておらず、FGFR3病に十分な治療が行い得るかについては不明な点も多いため、更なる新規治療薬の開発が切望されている。 For example, 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. However, it has been confirmed only in transformed cells into which mutant FGFR3 has been introduced, its effectiveness has not been confirmed using an appropriate human cell model, and it is unclear whether sufficient treatment can be performed for FGFR3 disease. Therefore, the development of further new therapeutic agents is eagerly desired.
本発明者らは、FGFR3病患者由来の体細胞を用いて作製したiPS細胞を利用して治療薬の候補を探索し、高脂血症治療薬であるスタチン類がFGFR3病の治療薬の候補となり得ることを報告している(特許文献1および非特許文献4)。 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).
本発明の課題は、線維芽細胞増殖因子受容体3(FGFR3)病の治療剤および/または予防剤を提供することにある。 An object of the present invention is to provide a therapeutic and / or prophylactic agent for fibroblast growth factor receptor 3 (FGFR3) disease.
本発明者は上記の課題を解決すべくFGFR3病の治療剤および/または予防剤を見出すべくFGFR3病患者の体細胞由来のiPS細胞を用いてスクリーニングを行った結果、メトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤が当該FGFR3病患者由来のiPS細胞から軟骨細胞への分化誘導を促進することを見出した。本発明はそのような知見に基づいて完成されたものである。 As a result of screening using iPS cells derived from somatic cells of FGFR3 disease patients in order to find a therapeutic and / or preventive agent for FGFR3 disease in order to solve the above problems, 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. The present invention has been completed based on such findings.
すなわち、本発明は次に記載の事項を提供するものである。
[1] 有効成分としてFarnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤から成る群より選択される少なくとも1つの薬剤を含む、FGFR3病の治療および/または予防用医薬。
[2] 前記薬剤がメトホルミンである、[1]に記載の医薬。
[3] 前記Farnesyl transferase阻害剤が、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 Dihydrochloride、Manumycin A、Tipifarnibおよびα-hydroxy Farnesyl Phosphonic Acidから成る群より選択される薬剤である、[1]に記載の医薬。
[4] 前記Geranylgeranyl transferase阻害剤が、GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297およびGGTI-298から成る群より選択される薬剤である、[1]に記載の医薬。
[5] 前記Rock阻害剤が、Y-27632、Fasudil/HA1077、SR3677、GSK269962、H-1152およびWf-536から成る群より選択される薬剤である、[1]に記載の医薬。
[6] 前記FGFR3病が、致死性骨異形成症 (TD) および/または軟骨無形成症 (ACH)である、[1]から[5]のいずれか一つに記載の医薬。
[7] FGFR3病を治療および/または予防するための方法であって、メトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤から成る群より選択される少なくとも1つの薬剤を投与することを含む、方法。
[8] 前記薬剤がメトホルミンである、[7]に記載の方法。
[9] 前記Farnesyl transferase阻害剤が、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 Dihydrochloride、Manumycin A、Tipifarnibおよびα-hydroxy Farnesyl Phosphonic Acidから成る群より選択される薬剤である、[7]に記載の方法。
[10] 前記Geranylgeranyl transferase阻害剤が、GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297およびGGTI-298から成る群より選択される薬剤である、[7]に記載の方法。
[11] 前記Rock阻害剤が、Y-27632、Fasudil/HA1077、SR3677、GSK269962、H-1152およびWf-536から成る群より選択される薬剤である、[7]に記載の方法。
[12] 前記FGFR3病が、致死性骨異形成症 (TD) および/または軟骨無形成症 (ACH)である、[7]から[11]のいずれか一つに記載の方法。
[13] FGFR3病の治療および/または予防用医薬の製造におけるメトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤から成る群より選択される少なくとも1つの薬剤の使用。
[14] 前記薬剤がメトホルミンである、[13]に記載の使用。
[15] 前記Farnesyl transferase阻害剤が、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 Dihydrochloride、Manumycin A、Tipifarnibおよびα-hydroxy Farnesyl Phosphonic Acidから成る群より選択される薬剤である、[13]に記載の使用。
[16] 前記Geranylgeranyl transferase阻害剤が、GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297およびGGTI-298から成る群より選択される薬剤である、[13]に記載の使用。
[17] 前記Rock阻害剤が、Y-27632、Fasudil/HA1077、SR3677、GSK269962、H-1152およびWf-536から成る群より選択される薬剤である、[13]に記載の使用。
[18] 前記FGFR3病が、致死性骨異形成症 (TD) および/または軟骨無形成症 (ACH)である、[13]から[17]のいずれか一つに記載の使用。
[19] FGFR3病を治療および/または予防するために使用されるメトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤から成る群より選択される少なくとも1つの薬剤。
[20] 前記薬剤がメトホルミンである、[19]に記載の薬剤。
[21] 前記Farnesyl transferase阻害剤が、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 Dihydrochloride、Manumycin A、Tipifarnibおよびα-hydroxy Farnesyl Phosphonic Acidから成る群より選択される薬剤である、[19]に記載の薬剤。
[22] 前記Geranylgeranyl transferaseが、GGTI-2418, GGTI-2133, GGTI-2147, GGTI-2154, GGTI-2166, GGTI-286, GGTI-287, GGTI-297およびGGTI-298から成る群より選択される薬剤である、[19]に記載の薬剤。
[23] 前記Rock阻害剤が、Y-27632、Fasudil/HA1077、SR3677、GSK269962、H-1152およびWf-536から成る群より選択される薬剤である、[19]に記載の薬剤。
[24] 前記FGFR3病が、致死性骨異形成症 (TD) および/または軟骨無形成症 (ACH)である、[19]から[23]のいずれか一つに記載の薬剤。That is, the present invention provides the following matters.
[1] 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.
[2] The medicament according to [1], wherein the drug is metformin.
[3] 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 α-hydroxy Farnesyl Phosphonic Acid.
[4] 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.
[5] The medicament according to [1], wherein the Rock inhibitor is a drug selected from the group consisting of Y-27632, Fasudil / HA1077, SR3677, GSK269962, H-1152 and Wf-536.
[6] The medicament according to any one of [1] to [5], wherein the FGFR3 disease is lethal osteodysplasia (TD) and / or achondroplasia (ACH).
[7] 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.
[8] The method according to [7], wherein the drug is metformin.
[9] 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 α-hydroxy Farnesyl Phosphonic Acid.
[10] 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.
[12] The method according to any one of [7] to [11], wherein the FGFR3 disease is lethal osteodysplasia (TD) and / or achondroplasia (ACH).
[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.
[14] The use according to [13], wherein the drug is metformin.
[15] 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 use according to [13], which is a drug selected from the group consisting of Dihydrochloride, Manumycin A, Tipifarnnib and α-hydroxy Farnesyl Phosphonic Acid.
[16] 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 use according to [13], which is a drug to be used.
[17] The use according to [13], wherein the Rock inhibitor is a drug selected from the group consisting of Y-27632, Fasudil / HA1077, SR3677, GSK269962, H-1152 and Wf-536.
[18] The use according to any one of [13] to [17], wherein the FGFR3 disease is lethal osteodysplasia (TD) and / or achondroplasia (ACH).
[19] At least one drug selected from the group consisting of metformin, a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor, and a Rock inhibitor used to treat and / or prevent FGFR3 disease.
[20] The drug according to [19], wherein the drug is metformin.
[21] 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 α-hydroxy Farnesyl Phosphonic Acid.
[22] 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 drug according to [19], which is a drug.
[23] The drug according to [19], wherein the Rock inhibitor is a drug selected from the group consisting of Y-27632, Fasudil / HA1077, SR3677, GSK269962, H-1152 and Wf-536.
[24] The drug according to any one of [19] to [23], wherein the FGFR3 disease is lethal osteodysplasia (TD) and / or achondroplasia (ACH).
本発明により、FGFR3病の治療剤および/または予防剤を提供することが可能となる。 According to the present invention, it is possible to provide a therapeutic and / or prophylactic agent for FGFR3 disease.
FGFRの変異を有する疾患(例えば、FGFR3病)の治療剤および/または予防剤
本明細書において、「FGFR3病」は、FGFR3中に突然変異を有することにより骨形成異常を生じたあらゆる骨形成疾患を意味する。FGFR3病は、好ましくは、骨系統疾患の国際分類(Warman et al., Am J Med Genet 155A(5):943-68 (2011))に記載されたFGFR3病群に属する一連の疾患を意味し、例えば、致死性骨異形成症 (TD) 、軟骨無形成症 (ACH)、軟骨低形成症、Camptodactyly, tall stature, and hearing loss syndrome (CATSHL)、Crouzon-like craniosynostosis with acanthosis nigricans (Crouzonodermoskeletal)、頭蓋骨早期癒合症などが挙げられる。FGFR3中に生じる突然変異は、機能獲得型もしくは機能欠損型のいずれの変異であってもよいが、好ましくは、機能獲得型の突然変異であり得る。 Therapeutic and / or preventive agent for a disease having a mutation in FGFR (for example, FGFR3 disease) In the present specification, “FGFR3 disease” refers to any bone morphogenetic disease in which bone dysplasia is caused by having a mutation in FGFR3. Means. 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)). For example, lethal osteodysplasia (TD), achondroplasia (ACH), hypochondral dysplasia, Camptodactyly, tall stature, and hearing loss syndrome (CATSHL), 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.
本発明において、FGFRの変異を有する疾患(例えば、FGFR3病)の治療および/または予防剤は、メトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤から成る群より選択される少なくとも1つの薬剤を有効成分として含む医薬である。有効成分はメトホルミンおよびFarnesyl transferase阻害剤から成る群より選択される少なくとも1つの薬剤であってもよく、メトホルミンであってもよい。 In the present invention, the therapeutic and / or preventive agent for a disease having an FGFR mutation (for example, FGFR3 disease) is at least one selected from the group consisting of metformin, a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor, and a 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.
メトホルミン(化学名:1,1-Dimethylbiguanide、CAS番号:657-24-9、C4H11N5)は、ビグアナイド系の血糖降下薬として知られている。メトホルミン塩酸塩が製剤化され上市されている。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.
本発明におけるFarnesyl transferase阻害剤はFarnesyl transferaseの機能を抑制できるものである限り特に限定されず、例えば、Lonafarnib(CAS番号:193275-84-2、C27H31Br2ClN4O2、例、Shen M et al., Drug Discov Today 20, 267-276 (2015)参照)、Chaetomellic acid A(CAS番号:148796-51-4、C19H32O4 2Na、例、J.B. Gibbs, et al.; J. Biol. Chem. 268, 7617 (1993)、 F. Tamanoi; Trends Biochem. Sci. 18, 349 (1993) 参照)、FPT Inhibitor I(C19H29NO6P 3Na、例、Manne, V., et al. 1995. Drug Development Res. 34, 121、Patel, D.V., et al. 1995. J. Med. Chem. 38, 2906参照)、FPT Inhibitor II(C17H28NO5P 2Na、例、Manne, V., et al. 1995. Drug Development Res. 34, 121参照)、FPT Inhibitor III(C23H39NO7P Na、例、Wang, D., et al. 1998. J. Biol. Chem. 273, 33027、Manne, V., et al. 1995. Drug Development Res. 34, 121参照)、FTase Inhibitor I(CAS番号:149759-96-6、C22H38N4O3S2、例、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): 18415-8参照)、FTase Inhibitor II(CAS番号:156707-43-6、C15H21N3O4S2、例、Song, Jia L., et al., 2003 Microbiology (Reading, England). 149(Pt 1): 249-59参照)、FTI-276 trifluoroacetate salt(CAS番号:170006-72-1 (free base) 、C21H27N3O3S2 C2HF3O2、例、Cohen-Jonathan, E., et al., 1999 Radiation research. 152(4): 404-11参照)、FTI-277 trifluoroacetate salt(CAS番号:170006-73-2 (free base)、C22H29N3O3S2 xC2HF3O2、例、Cohen-Jonathan, E., et al., 1999 Radiation research. 152(4): 404-11参照)、L-744,832 Dihydrochloride(CAS番号:1177806-11-9、C26H45N3O6S2 2HCl、例、R.E. Barrington et al. Mol. Cell. Biol. 1998 18 85 2、L. Sepp-Lorenzo and N. Rosen J. Biol. Chem. 1998 273 20243 3、M.M. Moasser et al. Proc. Natl. Acad. Sci. USA 1998 95 1369参照)、Manumycin A(CAS番号:52665-74-4、C31H38N2O7、例、Hara, M., et al. 1993. Proc. Natl. Acad. Sci. U.S.A. 90: 2281-2285参照)、Tipifarnib(CAS番号:192185-72-1、C27H22Cl2N4O、例、Shen M et al., Drug Discov Today 20, 267-276 (2015)参照)およびα-hydroxy Farnesyl Phosphonic Acid(CAS番号:148796-53-6、C15H27O4P、例、Pompliano, D.L., Rands, E., Schaber, M.D., et al., Biochemistry 31 3800-3807 (1992) 参照)を含むが、これらに限定されない。The Farnesyl transferase inhibitor in the present invention is not particularly limited as long as it can suppress the function of Farnesyl transferase. For example, 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. 18, 349 (1993)), 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. 34, 121), 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). 149 (Pt 1 ): 249-59), 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. 152 (4): 404-11), L-744,832 Dihydrochloride (CAS number: 1177806-11-9, C 26 H 45 N 3 O 6 S 2 2HCl, e.g., RE Barrington et al. Mol. Cell. Biol. 1998 18 85 2, L. Sepp-Lorenzo and N. Rosen J. Biol. Chem. 1998 273 20243 3, MM Moasser et al. Proc. Natl. Acad. Sci. USA 1998 95 1369), Man umycin A (CAS number: 52665-74-4, C 31 H 38 N 2 O 7 , eg Hara, M., et al. 1993. Proc. Natl. Acad. Sci. USA 90: 2281-2285), 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 α-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.
本発明におけるGeranylgeranyl transferase阻害剤はGeranylgeranyl transferaseの機能を抑制できるものである限り特に限定されず、例えば、GGTI-2418(CAS番号:171744-11-9、C23H31N3O3S、例、Shen M et al., Drug Discov Today 20, 267-276 (2015)参照)、GGTI-2133(CAS番号:191102-79-1、C27H28N4O3 C2HF3O2、例、Shen M et al., Drug Discov Today 20, 267-276 (2015)参照)、GGTI-2147(CAS番号:191102-87-1、C28H30N4O3、例、Bernot, D., et al. 2003. J. Cardiovasc. Pharmacol. 41, 316 参照)、GGTI-2154(CAS番号:251577-10-3、例、Shen M et al., Drug Discov Today 20, 267-276 (2015)参照)、GGTI-2166(日化辞番号:J1.244.741H、C25H30N4O3)、GGTI-286(CAS番号:171744-11-9、C23H31N3O3S、例、Lerner, E C., et al., 1995 The Journal of biological chemistry. 270(45): 26770-3 参照)、GGTI-287(C22H29N3O3S、例、Shen M et al., Drug Discov Today 20, 267-276 (2015)参照)、GGTI-297(CAS番号:181045-83-0、C26H31N3O3S C2HF3O2、例、Sun, J., et al. 1998. Oncogene 16, 1467参照)およびGGTI-298(CAS番号:180977-44-0、C27H33N3O3S CF3CO2H、例、McGuire, T F., et al., 1996 The Journal of biological chemistry. 271(44): 27402-7 参照)を含むが、これらに限定されない。The Geranylgeranyl transferase inhibitor in the present invention is not particularly limited as long as it can suppress the function of Geranylgeranyl transferase. For example, 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. See J. Cardiovasc. Pharmacol. 41, 316), 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) Lerner, E C., et al., 1995 The Journal of biological chemistry. 270 (45): 26770-3), GGTI-287 (C 22 H 29 N 3 O 3 S, eg, Shen M et al. , Drug Discov Today 20, 267-276 (2015) Irradiation), GGTI-297 (CAS Number:. 181045-83-0, C 26 H 31 N 3 O 3 SC 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.
本発明におけるRock阻害剤は、Rho-キナーゼ(ROCK)の機能を抑制できるものである限り特に限定されず、例えば、Y-27632(例、Ishizaki et al., Mol. Pharmacol. 57, 976-983 (2000);Narumiya et al., Methods Enzymol. 325,273-284 (2000)参照)、Fasudil/HA1077(例、Uenata et al., Nature 389: 990-994 (1997)参照)、SR3677(例、Feng Y et al., J Med Chem. 51: 6642-6645(2008)参照)、GSK269962(例、Stavenger RA et al., J Med Chem. 50: 2-5 (2007)またはWO2005/037197参照)、H-1152(例、Sasaki et al., Pharmacol. Ther. 93: 225-232 (2002)参照)、Wf-536(例、Nakajima et al., Cancer Chemother Pharmacol. 52(4): 319-324 (2003)参照)およびそれらの誘導体、ならびにROCKに対するアンチセンス核酸、RNA干渉誘導性核酸(例、siRNA)、ドミナントネガティブ変異体、およびそれらの発現ベクターが挙げられる。また、ROCK阻害剤としては他の公知の低分子化合物も使用できる(例えば、米国特許出願公開第2005/0209261号、同第2005/0192304号、同第2004/0014755号、同第2004/0002508号、同第2004/0002507号、同第2003/0125344号、同第2003/0087919号、及び国際公開第2003/062227号、同第2003/059913号、同第2003/062225号、同第2002/076976号、同第2004/039796号参照)。本発明では、1種または2種以上のROCK阻害剤が使用され得る。 The Rock inhibitor in the present invention is not particularly limited as long as it can suppress the function of Rho-kinase (ROCK). For example, 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, see Stavenger RA et al., J Med Chem. 50: 2-5 (2007) or WO2005 / 037197), 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) And derivatives thereof, as well as antisense nucleic acids to ROCK, RNA interference inducing nucleic acids (eg, siRNA), dominant negative mutants, 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). 2004/0002507, 2003/0125344, 2003/0087919, and International Publications 2003/062227, 2003/059913, 2003/062225, 2002/076976 No., 2004/039796). In the present invention, one or more ROCK inhibitors may be used.
なお、本発明のメトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤またはRock阻害剤は、その薬理学的に許容される塩(好ましくは、塩酸塩、ナトリウム塩またはカルシウム塩)を包含する。 The 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).
メトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤またはRock阻害剤をFGFR3病の治療剤および/または予防剤として使用する場合、常套手段に従って製剤化することができる。例えば、経口投与のための組成物としては、固体または液体の剤形、具体的には錠剤(糖衣錠、フィルムコーティング錠を含む)、丸剤、顆粒剤、散剤、カプセル剤(ソフトカプセル剤を含む)、シロップ剤、乳剤、懸濁剤等が挙げられる。一方、非経口投与のための組成物としては、例えば、注射剤、坐剤等が用いられ、注射剤は静脈注射剤、皮下注射剤、皮内注射剤、筋肉注射剤、点滴注射剤等の剤形を包含しても良い。これらの製剤は、賦形剤(例えば、乳糖、白糖、葡萄糖、マンニトール、ソルビトールのような糖誘導体;トウモロコシデンプン、バレイショデンプン、α澱粉、デキストリンのような澱粉誘導体;結晶セルロースのようなセルロース誘導体;アラビアゴム;デキストラン;プルランのような有機系賦形剤;および、軽質無水珪酸、合成珪酸アルミニウム、珪酸カルシウム、メタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体;燐酸水素カルシウムのような燐酸塩;炭酸カルシウムのような炭酸塩;硫酸カルシウムのような硫酸塩等の無機系賦形剤である)、滑沢剤(例えば、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウムのようなステアリン酸金属塩;タルク;コロイドシリカ;ビーズワックス、ゲイ蝋のようなワックス類;硼酸;アジピン酸;硫酸ナトリウムのような硫酸塩;グリコール;フマル酸;安息香酸ナトリウム;DLロイシン;ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウムのようなラウリル硫酸塩;無水珪酸、珪酸水和物のような珪酸類;および、上記澱粉誘導体である)、結合剤(例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール、および、前記賦形剤と同様の化合物である)、崩壊剤(例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体;カルボキシメチルスターチ、カルボキシメチルスターチナトリウム、架橋ポリビニルピロリドンのような化学修飾されたデンプン・セルロース類である)、乳化剤(例えば、ベントナイト、ビーガムのようなコロイド性粘土;水酸化マグネシウム、水酸化アルミニウムのような金属水酸化物;ラウリル硫酸ナトリウム、ステアリン酸カルシウムのような陰イオン界面活性剤;塩化ベンザルコニウムのような陽イオン界面活性剤;および、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ショ糖脂肪酸エステルのような非イオン界面活性剤である)、安定剤(メチルパラベン、プロピルパラベンのようなパラオキシ安息香酸エステル類;クロロブタノール、ベンジルアルコール、フェニルエチルアルコールのようなアルコール類;塩化ベンザルコニウム;フェノール、クレゾールのようなフェノール類;チメロサール;デヒドロ酢酸;および、ソルビン酸である)、矯味矯臭剤(例えば、通常使用される、甘味料、酸味料、香料等である)、希釈剤等の添加剤を用いて周知の方法で製造される。 When metformin, a Farnesyl transferase inhibitor, a Geranylgeranyl transferase inhibitor or a Rock inhibitor is used as a therapeutic and / or prophylactic agent for FGFR3 disease, it can be formulated according to conventional means. For example, 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. On the other hand, as a composition 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 sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; anhydrous silicic acid, silicic acid hydrate Such as silicic acids; and the above-mentioned starch derivatives), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the excipients), disintegrants ( For example, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; carboxymethyl starch, carboxymethyl starch sodium, Chemically modified starches and celluloses such as cross-linked polyvinyl pyrrolidone), emulsifiers (eg, colloidal clays such as bentonite and bee gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; sodium lauryl sulfate Anionic surfactants such as calcium stearate; cationic surfactants such as benzalkonium chloride; and nonionic interfaces such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters Activators), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol, Phenols such as alcohol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (for example, commonly used sweeteners, acidulants, fragrances, etc.), additives such as diluents Is manufactured by a well-known method.
本発明の薬剤の患者への投与量は、治療すべき病態の種類、症状および疾患の重篤度、患者年齢、性別もしくは体重、投与法などにより異なるので一義的には言えないが、医師が前記状況を考慮して判断することにより、適宜適当な投与量を決定することができる。 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.
経口投与の場合には、例えば、1回あたり下限0.1mg(好ましくは、0.5mg)、上限1000mg(好ましくは、500mg)を、非経口的投与の場合には、1回あたり下限0.01mg(好ましくは、0.05mg)、上限100mg(好ましくは、50mg)を、成人に対して1日あたり1から6回投与することができる。症状に応じて増量もしくは減量してもよい。 In the case of oral administration, for example, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 1000 mg (preferably 500 mg). In the case of parenteral administration, 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.
本発明を以下の実施例でさらに具体的に説明するが、本発明の範囲はそれら実施例に限定されないものとする。 The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.
実施例1
iPS細胞の作製
以下のすべての実験は、治験審査委員会、動物実験委員会および施設内生物安全委員会、ならびに京都大学の承認を得て行われた。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.
TD患者由来のヒト皮膚線維芽細胞(TD714, TD10749, TD315HおよびTD329N) を、コリエル医学研究所および埼玉県立小児医療センターから入手した。これらのヒト皮膚線維芽細胞(HDF)から抽出したゲノムDNAを配列解析したところ、すべてのTD患者においてFGFR3遺伝子のヘテロ接合突然変異(Arg248Cys)が確認された。ACH患者由来のHDFとして、FGFR3遺伝子においてGly380Argのヘテロ接合突然変異を有する2人のACH患者のHDF(ACH8857およびACH8858)、およびACHよりも重篤な軟骨形成不全を示すHDF(ACHhomo-8859)をコリエル医学研究所より入手した。各患者由来のHDFから以下に記載する方法でiPS細胞を作製した。対照iPS細胞として、K. OkitaおよびS. Yamanaka(京都大学iPS細胞研究所)から入手した健常な個体由来のiPS細胞株(409B2)(Okita, K., et al. Nature methods 8, 409-412 (2011))を用いた。 Human dermal fibroblasts (TD714, TD10749, TD315H, and TD329N) from TD patients were obtained from the Coryell Institute for Medical Research 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細胞の製造は、次の方法によって行った。詳細には、入手したそれぞれのヒト線維芽細胞(HDF)を、10% FBS (Invitrogen), 50 U/ml penicillinおよび50 μg/ml streptomycinを添加したDMEM (Sigma)で培養した。続いて、Neon transfection system (Invitrogen)により、エピソーマルプラスミドベクター(Mixture Y4: OCT3/4, SOX2, KLF4, L-MYC, LIN28およびp53 shRNA)を各HDFにエレクトロポレーションで導入した(Okita, K., et al. Nature methods 8, 409-412 (2011))。1週間後に、フィーダー細胞をあらかじめ播種しておいた100 mmディッシュに1×105個の当該ベクターを導入したHDFを播種した。次いで、hiPSC培地(20% KSR(Invitrogen), 2mM L-グルタミン(Invitrogen), 1×10-4M 非必須アミノ酸(Invitrogen), 1×10-4M 2-メルカプトエタノール(Invitrogen), 50units/ml ペニシリン(Invitrogen), 50μg/ml ストレプトマイシン(Invitrogen), 4ng/ml bFGF(WAKO)を添加したDMEM/F12 (Sigma))で培養した。得られた各iPS細胞は、抗SSEA4抗体(Santa Cruz, sc-5279)および抗-TRA1-60抗体(Abcam, ab16287)を用いた免疫組織化学により評価した。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 μg / 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)). One week later, 1 × 10 5 HDFs into which the vector was introduced were seeded on 100 mm dishes in which feeder cells had been seeded in advance. Next, hiPSC medium (20% KSR (Invitrogen), 2 mM L-glutamine (Invitrogen), 1 × 10 −4 M non-essential amino acid (Invitrogen), 1 × 10 −4 M 2-mercaptoethanol (Invitrogen), 50 units / ml The cells were cultured in penicillin (Invitrogen), 50 μg / ml streptomycin (Invitrogen), 4 ng / ml bFGF (WAKO) -added DMEM / F12 (Sigma)). Each obtained iPS cell was evaluated by immunohistochemistry using an anti-SSEA4 antibody (Santa Cruz, sc-5279) and an anti-TRA1-60 antibody (Abcam, ab16287).
その結果、作製されたすべてのiPSC株はES細胞マーカー(SSEA4およびTRA1-60)を発現しており、三胚葉を含むテラトーマを形成することが確認された。 As a result, it was confirmed that all iPSC strains produced expressed ES cell markers (SSEA4 and TRA1-60) and formed teratomas including three germ layers.
mRNAの測定
RNAは、RNeasy Mini Kit (Qiagen)を用いて、各細胞から単離した。得られた全RNAのうち500 ngを鋳型として、ReverTra Ace (TOYOBO)を用いて逆転写によりcDNAを合成した。定量PCR(リアルタイムPCR)のための標準曲線を作成して解析を行った。リアルタイムPCR解析は、KAPA SYBR FAST qPCR kit Master Mix ABI prism (KAPA BIOSYSTEMS)を用いて、Step One system (ABI)により測定した。mRNAの発現量は、b-ACTINの発現量で校正した。使用したプライマーの配列を表1に示す。 mRNA measurement
RNA was isolated from each cell using the RNeasy Mini Kit (Qiagen). CDNA was synthesized by reverse transcription using ReverTra Ace (TOYOBO) using 500 ng of the obtained total RNA as a template. A standard curve for quantitative PCR (real-time PCR) was prepared and analyzed. Real-time PCR analysis was performed by Step One system (ABI) using KAPA SYBR FAST qPCR kit Master Mix ABI prism (KAPA BIOSYSTEMS). The expression level of mRNA was calibrated with the expression level of b-ACTIN. The primer sequences used are shown in Table 1.
実施例2
軟骨誘導
以前に報告された方法(Oldershaw, R.A., et al., Nat Biotechnol 28, 1187-1194 (2010))を修正した以下に記載の方法に従って、各iPS細胞から軟骨細胞に分化誘導した。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)).
各iPS細胞をマトリゲル(Invitrogen)コートディッシュ上に播種し、Essential 8培地(Life Technologies)に50units/ml ペニシリンおよび50μg/ml ストレプトマイシンを添加した培地を加え、フィーダーフリー条件下で未分化維持培養した。播種後10〜15日目に、1〜2×105細胞から成るコロニーを中胚葉分化培地(DMEM/F12に対し10ng/ml Wnt3A(R&D), 10ng/ml アクチビンA(R&D), 1% インスリン-トランスフェリン-亜セレン酸ナトリウム(Invitrogen), 1% 牛胎児血清, 50units/ml ペニシリン, 50μg/ml ストレプトマイシンを混合して調製)に交換した(分化誘導0日目)。3日後(分化誘導3日目)、各薬剤(1μMのロスバスタチン(BioVision, 1995-5)、各濃度(0.1μM、1μMまたは10μM)のFarnesyl transferase阻害剤(FTI-277)(Sigma)(以下、FTIという)、各濃度(0.1μM、1μMまたは10μM)のGeranylgeranyl transferase阻害剤(GGTI-287)(Sigma)(以下、GGTIという)、各濃度(0.1μM、1μM、10μMまたは100μM)のRock阻害剤(Y27632)(Wako)(以下、Rockiという))を添加した軟骨分化培地(50μg/mlアスコルビン酸、10ng/ml BMP2(Osteopharma)、10ng/ml TGFβ(Pepro Tech)、10ng/ml GDF5、1% インスリン-トランスフェリン-亜セレン酸ナトリウム、1% FBS、50units/ml ペニシリンおよび 50μg/ml ストレプトマイシンを含有するDMEM/F12)または低コレステロール軟骨分化培地(上記軟骨分化培地のFBSを低コレステロールFBSへ置換した培地)に交換し、11日後(分化誘導14日目)にディッシュから細胞を引き剥がした。同じ培地を用いて浮遊培養により28日間培養し、パーティクルを回収した(分化誘導42日目)。分化誘導中は、2〜7日ごとに培地を交換した。Each iPS cell was seeded on a Matrigel (Invitrogen) coated dish, a medium supplemented with 50 units / ml penicillin and 50 μg / ml streptomycin was added to Essential 8 medium (Life Technologies), and cultured under feeder-free conditions. 10-15 days after seeding, 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 μg / ml prepared by mixing streptomycin) (Day 0 of differentiation induction). Three days later (differentiation induction day 3), each drug (1 μM rosuvastatin (BioVision, 1995-5), each concentration (0.1 μM, 1 μM or 10 μM) 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 μM, 1 μM or 10 μM), Rock inhibitor at each concentration (0.1 μM, 1 μM, 10 μM or 100 μM) (Y27632) (Wako) (hereinafter referred to as Rocki)) cartilage differentiation medium (50 μg / ml ascorbic acid, 10 ng / ml BMP2 (Osteopharma), 10 ng / ml TGFβ (Pepro Tech), 10 ng / ml GDF5, 1% Insulin-transferrin-sodium selenite, 1% FBS, DMEM / F12 containing 50 units / ml penicillin and 50 μg / ml streptomycin or low cholesterol cartilage differentiation medium (medium in which FBS in the above cartilage differentiation medium is replaced with low cholesterol FBS 11 days later (differentiation invitation) The cells were peeled off from the dish on day 14). The particles were collected by floating culture using the same medium for 28 days (differentiation induction day 42). During differentiation induction, the medium was changed every 2 to 7 days.
別途、上記と同じ方法で、3種類のFarnesyl transferase阻害剤を用いて各iPS細胞から軟骨細胞に分化誘導した。すなわち、分化誘導3日目にFTI-277(Sigma)(以下、FTIという)、Lonafarnib(Cayman)(以下、Lonaという)およびTipifarnib(LCL)(以下、Tipiという)をそれぞれ濃度0.0001μM、0.001μM、0.01μMまたは0.1μMで添加した軟骨分化培地に交換し、分化誘導14日目にディッシュから細胞を引き剥がし、同じ培地を用いて浮遊培養により28日間培養し、分化誘導42日目にパーティクルを回収した。 Separately, differentiation was induced from each iPS cell to a chondrocyte using three types of Farnesyl transferase inhibitors in the same manner as described above. That is, on the third day of differentiation induction, FTI-277 (Sigma) (hereinafter referred to as FTI), Lonafarnib (Cayman) (hereinafter referred to as Lona) and Tipifarnib (LCL) (hereinafter referred to as Tipi) at concentrations of 0.0001 μM and 0.001 μM, respectively. The culture medium was replaced with a cartilage differentiation medium added at 0.01 μM or 0.1 μM, 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.
得られたパーティクル内に存在する軟骨細胞における、軟骨細胞マーカーであるSOX9および軟骨マトリックスタンパク質をコードする遺伝子(II型コラーゲン(COL2A1)およびアグリカン(Acan))のmRNAの発現量をリアルタイムPCRで調べた。さらに、得られたパーティクルをサフラニンO染色し、サフラニンO陽性の軟骨組織の存在を確認すると共に、サフラニンO陽性領域の比率を求めた。 In the chondrocytes present in the obtained particles, 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. . Furthermore, 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.
(1)TD714由来iPS細胞の結果
図1にTD714由来iPS細胞から、Farnesyl transferase阻害剤(FTI-277)、Geranylgeranyl transferase阻害剤(GGTI-287)、またはRock阻害剤(Y27632)を添加した培地を用いて分化誘導した軟骨細胞における軟骨細胞マーカーをリアルタイムPCRで測定した結果を示した。(A)がSOX9、(B)がCOL2A1、(C)がAcanの結果である。いずれの薬剤を用いた場合でも、Vehicle(基剤)と比較して各遺伝子の発現を上昇させることが確認された。(1) Results of TD714-derived iPS cells 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). The results of measuring the chondrocyte markers in the chondrocytes induced to differentiate by real-time PCR are shown. (A) is the result of SOX9, (B) is the result of COL2A1, and (C) is the result of Acan. In any case, it was confirmed that the expression of each gene was increased as compared with Vehicle (base).
図2、図3および図4に、TD714由来iPS細胞から、Farnesyl transferase阻害剤(FTI-277)、Geranylgeranyl transferase阻害剤(GGTI-287)、またはRock阻害剤(Y27632)を添加した培地を用いて分化誘導したパーティクルをサフラニンO染色した結果を示した。いずれの薬剤を用いた場合でも、サフラニンO陽性の軟骨組織が確認された。 2, 3, and 4, using a medium supplemented with a Farnesyl transferase inhibitor (FTI-277), Geranylgeranyl transferase inhibitor (GGTI-287), or Rock inhibitor (Y27632) from TD714-derived iPS cells. The results of the differentiation-induced particles were stained with safranin O. Safranin O-positive cartilage tissue was confirmed when any drug was used.
図5にTD714由来iPS細胞から、3種類のFarnesyl transferase阻害剤(FTI-277、LonafarnibおよびTipifarnib)をそれぞれ添加した培地を用いて分化誘導した軟骨細胞における軟骨細胞マーカーをリアルタイムPCRで測定した結果を示した。(A)がSOX9、(B)がCOL2A1、(C)がAcanの結果である。いずれのFarnesyl transferase阻害剤を用いた場合でも、Vehicle(基剤)と比較して各遺伝子の発現を上昇させることが確認された。 Fig. 5 shows the results of real-time PCR measurement of chondrocyte markers in chondrocytes induced by differentiation using 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 expression of each gene was increased as compared with Vehicle (base).
図6および図7に、TD714由来iPS細胞から、3種類のFarnesyl transferase阻害剤(FTI-277、LonafarnibおよびTipifarnib)をそれぞれ添加した培地を用いて分化誘導したパーティクルをサフラニンO染色した結果を示した。いずれのFarnesyl transferase阻害剤を用いた場合でも、サフラニンO陽性の軟骨組織が確認された。 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.
(2)TD329N由来iPS細胞の結果
図8および図9に、TD329N由来iPS細胞から、Farnesyl transferase阻害剤(FTI-277)、Geranylgeranyl transferase阻害剤(GGTI-287)、またはRock阻害剤(Y27632)を添加した培地を用いて分化誘導したパーティクルをサフラニンO染色した結果を示した。いずれの薬剤を用いた場合でも、サフラニンO陽性の軟骨組織が確認された。(2) Results of TD329N-derived iPS cells In FIGS. 8 and 9, a Farnesyl transferase inhibitor (FTI-277), a Geranylgeranyl transferase inhibitor (GGTI-287), or a Rock inhibitor (Y27632) is obtained from TD329N-derived iPS cells. 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.
図10にTD329N由来iPS細胞から、3種類のFarnesyl transferase阻害剤(FTI-277、LonafarnibおよびTipifarnib)をそれぞれ添加した培地を用いて分化誘導した軟骨細胞における軟骨細胞マーカーをリアルタイムPCRで測定した結果を示した。(A)がSOX9、(B)がCOL2A1、(C)がAcanの結果である。いずれのFarnesyl transferase阻害剤を用いた場合でも、Vehicle(基剤)と比較して各遺伝子の発現を上昇させることが確認された。 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 expression of each gene was increased as compared with Vehicle (base).
(3)ACH8858由来iPS細胞の結果
図11および図12に、ACH8858由来iPS細胞から、Farnesyl transferase阻害剤(FTI-277)、Geranylgeranyl transferase阻害剤(GGTI-287)、またはRock阻害剤(Y27632)添加した培地を用いて分化誘導したパーティクルをサフラニンO染色した結果を示した。いずれの薬剤を用いた場合でも、サフラニンO陽性の軟骨組織が確認された。(3) Results of ACH8858-derived iPS cells 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. The results are shown in which the particles induced to differentiate using the prepared medium were stained with safranin O. Safranin O-positive cartilage tissue was confirmed when any drug was used.
図13にACH8858由来iPS細胞から、3種類のFarnesyl transferase阻害剤(FTI-277、LonafarnibおよびTipifarnib)をそれぞれ添加した培地を用いて分化誘導した軟骨細胞における軟骨細胞マーカーをリアルタイムPCRで測定した結果を示した。(A)がSOX9、(B)がCOL2A1、(C)がAcanの結果である。いずれのFarnesyl transferase阻害剤を用いた場合でも、Vehicle(基剤)と比較して各遺伝子の発現を上昇させることが確認された。 Fig. 13 shows the results of real-time PCR measurement of chondrocyte markers in chondrocytes induced by differentiation from ACH8858-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 expression of each gene was increased as compared with Vehicle (base).
(4)ACHhomo-8859由来iPS細胞の結果
図14および図15に、ACHhomo-8859由来iPS細胞から、Farnesyl transferase阻害剤(FTI-277)、Geranylgeranyl transferase阻害剤(GGTI-287)、またはRock阻害剤(Y27632)添加した培地を用いて分化誘導したパーティクルをサフラニンO染色した結果を示した。いずれの薬剤を用いた場合でも、サフラニンO陽性の軟骨組織が確認された。(4) Results of ACHhomo-8859-derived iPS cells 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.
図16にACHhomo-8859由来iPS細胞から、3種類のFarnesyl transferase阻害剤(FTI-277、LonafarnibおよびTipifarnib)をそれぞれ添加した培地を用いて分化誘導した軟骨細胞における軟骨細胞マーカーをリアルタイムPCRで測定した結果を示した。(A)がSOX9、(B)がCOL2A1、(C)がAcanの結果である。いずれのFarnesyl transferase阻害剤を用いた場合でも、Vehicle(基剤)と比較して各遺伝子の発現を上昇させることが確認された。 In FIG. 16, chondrocyte markers in chondrocytes induced by differentiation from ACHhomo-8859-derived iPS cells using media supplemented with three types of Farnesyl transferase inhibitors (FTI-277, Lonafarnib and Tipifarnib) were measured by real-time PCR. Results are shown. (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 expression of each gene was increased as compared with Vehicle (base).
実施例3
被験薬剤をメトホルミンに変更した以外は実施例2と同じ方法で、TD714由来iPS細胞およびACH8858由来iPS細胞から軟骨細胞に誘導した。対照iPS細胞として、健常個体由来の409B2を用いた。メトホルミン(1,1-Dimethylbiguanide hydrochloride(sigma))の濃度は、0.2mM, 2mMまたは5mMとした。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.
図17にメトホルミンを添加した培地を用いて分化誘導したパーティクルをサフラニンO染色した結果を示した。TD714由来iPS細胞およびACH8858由来iPS細胞から分化誘導したパーティクルには、どちらももサフラニンO陽性の軟骨組織が確認された。 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.
図18にメトホルミンを添加した培地を用いて分化誘導した軟骨細胞における軟骨細胞マーカー(COL2A1、Acan、SOX9)をリアルタイムPCRで測定した結果を示した。各遺伝子の発現量は、TD714由来iPS細胞を1μMのロスバスタチンで分化誘導したときの発現量を1として、相対値で示した。メトホルミンの添加により、各遺伝子の発現を上昇させることが確認された。 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 μM rosuvastatin was 1. It was confirmed that the addition of metformin increases the expression of each gene.
以上の結果から、メトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤またはRock阻害剤を用いることで、TD患者由来のiPS細胞およびACH患者由来のiPS細胞からであっても軟骨組織を形成させることができることが確認された。従って、メトホルミン、Farnesyl transferase阻害剤、Geranylgeranyl transferase阻害剤およびRock阻害剤は、致死性骨異形成症および軟骨無形成症の治療剤となり得ることが示唆された。 From the above results, 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.
本発明は、スクリーニングの結果得られた軟骨細胞への分化を促進する物質を提供するものであり、当該物質は、FGFR3病の新たな治療剤および/または予防剤として利用可能である。 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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