JP6908283B2 - Fgfr3病の予防または治療剤 - Google Patents
Fgfr3病の予防または治療剤 Download PDFInfo
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- JP6908283B2 JP6908283B2 JP2018509644A JP2018509644A JP6908283B2 JP 6908283 B2 JP6908283 B2 JP 6908283B2 JP 2018509644 A JP2018509644 A JP 2018509644A JP 2018509644 A JP2018509644 A JP 2018509644A JP 6908283 B2 JP6908283 B2 JP 6908283B2
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- ggti
- ips cells
- inhibitor
- fti
- fgfr3
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Description
[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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
Claims (2)
- 有効成分としてメトホルミンを含む、FGFR3の機能獲得型突然変異による骨形成異常を含む骨疾患の治療および/または予防用医薬。
- 前記FGFR3の機能獲得型突然変異による骨形成異常を含む骨疾患が、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、請求項1に記載の医薬。
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