CN115023231A - 软骨营养不良的治疗 - Google Patents
软骨营养不良的治疗 Download PDFInfo
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- CN115023231A CN115023231A CN202180011810.5A CN202180011810A CN115023231A CN 115023231 A CN115023231 A CN 115023231A CN 202180011810 A CN202180011810 A CN 202180011810A CN 115023231 A CN115023231 A CN 115023231A
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Abstract
本发明公开了一种用于治疗软骨发育不良的药物组合物,包括1‑[(3S)‑3‑[4‑氨基‑3‑[2‑(3,5‑二甲氧基苯基)乙炔基]‑1H‑吡唑并[3,4‑d]嘧啶‑1‑基]‑1‑吡咯烷基]‑2‑丙烯‑1‑酮或其药学上可接受的盐,以及使用该药物组合物的治疗方法。
Description
技术领域
相关申请的交叉引用
本申请要求2020年1月31日提交的第2020-014260号日本专利申请的优先权,其全部内容通过引用并入本文。
本发明涉及使用FGFR抑制剂治疗软骨发育异常(cartilage dysplasia)(软骨发育不全(achondroplasia)、软骨发育不良(cartilage hypoplasia)、致死性发育异常(thanatophoric dysplasia))。
背景技术
成纤维细胞生长因子(FGF)在各种组织中均有表达,是调节细胞增殖和分化的生长因子之一。FGF的生理活性由作为特定细胞表面受体的成纤维细胞生长因子受体(FGFR)介导。FGFR属于受体蛋白酪氨酸激酶家族,包括胞外配体结合结构域、单个跨膜结构域和胞内酪氨酸激酶结构域。迄今为止已经确定了四种类型的FGFR(FGFR1、FGFR2、FGFR3和FGFR4)。FGFR与FGF结合形成二聚体,并通过磷酸化激活。受体的激活诱导特定下游信号转导分子的动员和激活,从而发挥生理功能。
已经有一些关于FGF/FGFR信号转导异常与人类软骨细胞分化异常相关疾病之间关系的报道。在与人类软骨细胞分化异常相关的疾病中,FGF/FGFR信号转导的异常激活被认为是FGFR的基因突变导致的(非专利文献1和非专利文献2)。
在软骨发育异常中,已经有FGFR3中的G380R、N540K和K650E等位点突变的报道,并且提示这种基因突变可能是软骨发育异常的原因(非专利文献3、4和5)。另外,非专利文献6报道了FGFR抑制剂NVP-BGJ398对软骨发育不全的FGFR3Y367C/+小鼠模型具有治疗作用,其中FGFR3Y367C/+是激酶结构域外部的激活突变。此外,有报道表明NVP-BGJ398在50nM下对突变的FGFR3G380R/+具有激酶抑制作用。相反,没有关于对软骨发育不全的FGFR3G380R/+小鼠模型的治疗效果的报道。
专利文献1报道了具有FGFR抑制作用的二取代苯炔基化合物。专利文献2和3分别报道了这些化合物对具有特定FGFR2突变的癌症有效,并且在给药方案方面间歇给药可能是有效的。
引用列表:
专利文献:
专利文献1:WO2013/108809
专利文献2:WO2015/008844
专利文献3:WO2015/008839
非专利文献
非专利文献1:Dev.Dyn.2017Apr;246(4):291-309
非专利文献2:Am.J.Hum.Genet.2000Dec;67(6):1411-21
非专利文献3:Nature.1994Sep 15;371(6494):252-4
非专利文献4:Nat.Genet.1995Jul;10(3):357-9
非专利文献5:Am.J.Med.Genet.1996May 3;63(1):148-54
非专利文献6:J.Clin.Invest.2016 126(5):1871-1884
发明内容
技术问题:
本发明的目的在于提供一种治疗软骨发育异常的新药物,以及用该药物组合物的治疗方法。
问题的解决方案:
本发明的发明人进行大量研究以实现以上目的,并且发现1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮(Futibatinib)或其药学上可接受的盐抑制突变的FGFR3的磷酸化,并对软骨发育异常具有极好的骨延伸(bone extension)效果。
更具体地,本发明包括以下项[1]-[11]。
[1]一种用于治疗软骨发育异常的药物组合物,包括1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐。
[2]根据项[1]所述的药物组合物,其中所述软骨发育异常是软骨发育不全、软骨发育不良或致死性发育异常。
[3]根据项[1]或[2]所述的药物组合物,其中所述软骨发育异常是软骨发育不全。
[4]根据项[1]~[3]中任一项所述的药物组合物,其中所述软骨发育异常是具有FGFR3突变的软骨发育异常。
[5]根据项[4]所述的药物组合物,其中所述FGFR3突变是FGFR3中第248位精氨酸、第380位甘氨酸、第540位天冬酰胺或第650位赖氨酸的突变。
[6]根据项[4]所述的药物组合物,其中所述具有FGFR3突变的软骨发育异常是具有FGFR3突变的软骨发育不全。
[7]根据项[6]所述的药物组合物,其中所述软骨发育不全是具有FGFR3中的第380位甘氨酸突变为精氨酸的FGFR3突变的软骨发育不全。
[8]根据项[4]所述的药物组合物,其中所述具有FGFR3突变的软骨发育异常是具有FGFR3突变的软骨发育不良。
[9]根据项[8]所述的药物组合物,其中所述软骨发育不良是具有FGFR3中的第540位天冬酰胺突变为赖氨酸的FGFR3突变的软骨发育不良。
[10]根据项[4]所述的药物组合物,其中所述具有FGFR3突变的软骨发育异常是具有FGFR3突变的致死性发育异常。
[11]根据项[10]所述的药物组合物,其中所述致死性发育异常是具有FGFR3中的第248位精氨酸突变为半胱氨酸的FGFR3突变,或者第650位赖氨酸突变为谷氨酸的FGFR3突变的致死性发育异常。
本发明还涉及以下实施方式。
·一种用于治疗软骨发育异常的药剂,包括1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐。
·1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐,其用于治疗软骨发育异常。
·1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐用于治疗软骨发育异常的用途。
·1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐在制造用于治疗软骨发育异常的药物中的用途。
·一种治疗软骨发育异常的方法,包括将有效量的1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐施用于软骨发育异常患者的步骤。
·一种商业包装,包括作为活性成分的1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐,以及使用其治疗受试者中的软骨发育异常的说明书。
本发明的有利效果
本发明实现了对治疗软骨发育异常具有优异的骨延伸效果的治疗。
附图说明
图1示出股骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒(vehicle):ACH小鼠,溶媒给药组;ACH 0.1mg/kg:ACH小鼠,0.1mg/kg给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组。
图2示出胫骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 0.1mg/kg:ACH小鼠,0.1mg/kg给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组。
图3示出尺骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 0.1mg/kg:ACH小鼠,0.1mg/kg给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组。
图4示出股骨生长板软骨厚度的测量结果。纵轴表示生长板软骨的厚度(μm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 0.1mg/kg:ACH小鼠,0.1mg/kg给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组。
图5示出胫骨生长板软骨厚度的测量结果。纵轴表示生长板软骨的厚度(μm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 0.1mg/kg:ACH小鼠,0.1mg/kg给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组。
图6示出股骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组;ACH 10mg/kg:ACH小鼠,10mg/kg给药组。
图7示出胫骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组;ACH 10mg/kg:ACH小鼠,10mg/kg给药组。
图8示出尺骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组;ACH 10mg/kg:ACH小鼠,10mg/kg给药组。
图9示出股骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组;ACH 6mg/kg:ACH小鼠,6mg/kg给药组。
图10示出胫骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组;ACH 6mg/kg:ACH小鼠,6mg/kg给药组。
图11示出尺骨长度的测量结果。纵轴表示骨长(mm)。横轴如下:WT:野生型小鼠;ACH溶媒:ACH小鼠,溶媒给药组;ACH 1mg/kg:ACH小鼠,1mg/kg给药组;ACH 3mg/kg:ACH小鼠,3mg/kg给药组;ACH 6mg/kg:ACH小鼠,6mg/kg给药组。
图12示出使用来自致死性发育异常I型(TD1)和软骨无形性症(cartilageintangibility,ACH)患者的iPS细胞和葡糖胺聚糖作为指标的药效评价结果(番红染色图)。溶媒:溶媒(=0.1%DMSO)给药组;化合物1 1nM:1nM,化合物1给药组。
图13示出使用来自致死性发育异常I型(TD1)和软骨无形性症(ACH)患者的iPS细胞,以及COL2A和ACAN的mRNA表达为指标的药效评价结果。使用Step One Plus实时PCR系统(Step One Plus Real-Time PCR System,Applied Biosystems)进行测量。纵轴显示使用GAPDH基因作为内标的ΔCt值。横轴如下:溶媒:溶媒(=0.1%DMSO)给药组;化合物1:1nM,化合物1给药组。
具体实施方式
本发明涉及用于治疗软骨发育异常的药剂,包括1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐;用于治疗软骨发育异常的药物组合物,包括作为活性成分的1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐;以及使用该药物组合物的治疗方法。
1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮(在本说明书中以下称为“化合物1”)是具有以下结构的二取代苯炔基化合物。例如,该化合物可以根据WO2013/108809中描述的制备方法合成,但对方法没有特别限制。
在本发明中,化合物1可以直接使用,也可以以药学上可接受的盐的形式使用。化合物1的药学上可接受的盐没有特别限定,实例包括与无机酸例如盐酸、硫酸,或有机酸例如乙酸、柠檬酸、酒石酸、马来酸形成的加成盐;与碱金属例如钾和钠形成的盐;与碱土金属例如钙和镁形成的盐;与有机碱形成的盐例如铵盐、乙胺盐和精氨酸盐;和类似的盐。
在本发明中,“FGFR3”包括人或非人哺乳动物的FGFR3;优选人的FGFR3。人FGFR3的NCBI Gene ID编号为2261。此外,FGFR3蛋白质包括具有其剪接突变体的同种型。来源于人的同种型的实例包括由NCBI参考序列编码为:NP-000133的氨基酸序列(SEQ ID No.1)组成的多肽。
在本发明中,“FGFR3突变”没有特别限定,只要其是具有导致软骨发育异常的氨基酸突变的FGFR3蛋白质,或编码该氨基酸的基因。在具有SEQ ID No.1所示的氨基酸序列中至少一个选自第248位精氨酸、第380位甘氨酸、第540位天冬酰胺和第650位赖氨酸的氨基酸发生突变的氨基酸序列的FGFR3蛋白质的情况下,或者在具有不同于SEQ ID No.1的野生型氨基酸序列的FGFR蛋白质的情况下,优选具有在与SEQ ID No.1中的上述位置对应的位置处发生突变的氨基酸序列的FGFR3蛋白质,或者编码该氨基酸序列的FGFR3基因。
在具有SEQ ID No.1所示的氨基酸序列中至少一个选自第248位精氨酸、第380位甘氨酸和第650位赖氨酸的氨基酸发生突变的氨基酸序列的FGFR3蛋白质的情况下,或者在具有不同于SEQ ID No.1的野生型氨基酸序列的FGFR3蛋白质的情况下,更优选具有在与SEQ ID No.1中的上述位置对应的位置处发生突变的氨基酸序列的FGFR3蛋白质,或者编码该氨基酸序列的FGFR3基因。
在具有SEQ ID No.1所示的氨基酸序列中至少一个选自第248位精氨酸和第380位甘氨酸的氨基酸发生突变的氨基酸序列的FGFR3蛋白质的情况下,或者在具有不同于SEQID No.1的野生型氨基酸序列的FGFR3蛋白质的情况下,进一步更优选具有在与SEQ IDNo.1中的上述位置对应的位置处发生突变的氨基酸序列的FGFR3蛋白质,或者编码该氨基酸序列的FGFR3基因。
在具有SEQ ID No.1所示的氨基酸序列中第380位甘氨酸发生突变的氨基酸序列的FGFR3蛋白质的情况下,或者在具有不同于SEQ ID No.1的野生型氨基酸序列的FGFR蛋白质的情况下,再进一步更优选具有在SEQ ID No.1中的第380位的甘氨酸发生突变的氨基酸序列的FGFR3蛋白质,或者编码该氨基酸序列的FGFR3基因。
在本申请说明书中,对于某一FGFR3蛋白质,SEQ ID No.1所示的第X位氨基酸,除非另有说明,是指SEQ ID No.1所示的氨基酸序列中的第X个氨基酸,在具有不同于SEQ IDNo.1的野生型氨基酸序列的FGFR3蛋白质的情况下,是指与SEQ ID No.1中的第X位对应的位置处的氨基酸。例如,通过BLAST的多重比对,可以确认具有不同于SEQ ID No.1的野生型氨基酸序列的FGFR3蛋白质的某一氨基酸对应于SEQ ID No.1所示的哪个位置的氨基酸。
作为第380位的甘氨酸或者位于与SEQ ID No.1中的第380位对应的位置处的甘氨酸发生突变的FGFR3,优选第380位的甘氨酸或者对应位置处的甘氨酸突变为精氨酸的FGFR3。在本说明书中,第380位的甘氨酸或者位于与SEQ ID No.1中的第380位对应的位置处的甘氨酸发生突变的FGFR3有时被称为G380R。这同样适用于下述的R248C、N540K和K650E。作为第248位的精氨酸或者位于与SEQ ID No.1中的第248位对应的位置处的精氨酸发生突变的FGFR3,优选第248位的精氨酸或者对应位置处的精氨酸突变为半胱氨酸的R248C。作为第540位的天冬酰胺或者位于与SEQ ID No.1中的第540位对应的位置处的天冬酰胺发生突变的FGFR3,优选第540位的天冬酰胺或者对应位置处的天冬酰胺突变为赖氨酸的N540K。作为第650位的赖氨酸或者位于与SEQ ID No.1中的第650位对应的位置处的赖氨酸发生突变的FGFR3,优选第650位的赖氨酸或对应位置处的赖氨酸突变为谷氨酸的K650E。
FGFR3突变优选为具有含有至少一个选自R248C、G380R、N540K和K650E的氨基酸突变的氨基酸序列的FGFR3蛋白质,或编码该氨基酸序列的FGFR3基因;更优选为具有含有至少一个选自R248C、G380R和K650E的氨基酸突变的氨基酸序列的FGFR3蛋白质,或编码该氨基酸序列的FGFR3基因;进一步更优选为具有含有至少一个选自R248C和G380R的氨基酸突变的氨基酸序列的FGFR3蛋白质,或编码该氨基酸序列的FGFR3基因;再进一步更优选为具有G380R突变的FGFR3蛋白质,或编码该氨基酸序列的FGFR3基因。
如上所述,在某些FGFR3同种型的突变中,即使突变的位置由于氨基酸的缺失、插入等与SEQ ID No.1所示的氨基酸的位置不同,该突变也被认为与对应于SEQ ID No.1所示的氨基酸位置的位置相同。因此,例如,SEQ ID No.1所示的FGFR3中的第380位甘氨酸对应于具有NCBI参考序列:NP_001156685所示的氨基酸序列(SEQ ID No.2)的FGFR3中的第382位甘氨酸。因此,除非另有说明,在本发明中,“G380R”是指SEQ ID No.1所示的FGFR3中的第380位甘氨酸突变为精氨酸,以及具有NCBI参考序列:NP_001156685所示的氨基酸序列的FGFR3中的第382位甘氨酸突变为精氨酸。例如,通过BLAST的多重比对,可以确认某一FGFR3同种型的某一氨基酸对应于SEQ ID No.1所示的哪个位置的氨基酸。
在本发明中,“软骨发育异常”是指由生长软骨功能降低引起的疾病,例如,软骨发育不全、软骨发育不良和致死性发育异常;优选为软骨发育不全、软骨发育不良和致死性发育异常;更优选为软骨发育不全。
在本发明中,“具有FGFR3突变的软骨发育异常”是指由生长软骨功能降低引起的疾病,其中生长软骨功能降低是由以下突变导致的:SEQ ID No.1中第380位的甘氨酸或者位于与SEQ ID No.1中的第380位对应的位置处的甘氨酸的突变;第540位的天冬酰胺或者位于与SEQ ID No.1中的第540位对应的位置处的天冬酰胺的突变;第248位的精氨酸或者位于与SEQ ID No.1中的第248位对应的位置处的精氨酸的突变;或者第650位的赖氨酸或者位于与SEQ ID No.1中的第650位对应的位置处的赖氨酸的突变。
优选的实例包括具有第380位的甘氨酸或者位于与SEQ ID No.1中的第380位对应的位置处的甘氨酸突变为精氨酸的FGFR3突变的软骨发育不全;具有第540位的天冬酰胺或者位于与SEQ ID No.1中的第540位对应的位置处的天冬酰胺突变为赖氨酸的FGFR3突变的软骨发育不良;和具有第248位的精氨酸或者位于与SEQ ID No.1中的第248位对应的位置处的精氨酸突变为半胱氨酸的FGFR3突变,或者第650位的赖氨酸或者位于与SEQ ID No.1中的第650位对应的位置处的赖氨酸突变为谷氨酸的FGFR3突变的致死性发育异常。
更优选的实例包括具有第380位的甘氨酸或者位于与SEQ ID No.1中的第380位对应的位置处的甘氨酸突变为精氨酸的FGFR3突变的软骨发育不全;和具有第248位的精氨酸或者位于与SEQ ID No.1中的第248位对应的位置处的精氨酸突变为半胱氨酸的FGFR3突变,或者第650位的赖氨酸或者位于与SEQ ID No.1中的第650位对应的位置处的赖氨酸突变为谷氨酸的FGFR3突变的致死性发育异常。
进一步更优选的实例包括具有第380位的甘氨酸或者位于与SEQ ID No.1中的第380位对应的位置处的甘氨酸突变为精氨酸的FGFR3突变的软骨发育不全;和具有第248位的精氨酸或者位于与SEQ ID No.1中的第248位对应的位置处的精氨酸突变为半胱氨酸的FGFR3突变的致死性发育异常。
再进一步更优选的实例包括具有第380位的甘氨酸或者位于与SEQ ID No.1中的第380位对应的位置处的甘氨酸突变为精氨酸的FGFR3突变的软骨发育不全。
在本说明书中,有时将具有FGFR3突变的软骨发育异常简称为FGFR3突变软骨发育异常。
在本发明中,FGFR3突变可以通过本领域技术人员熟知的方法检测。FGFR3基因突变的检测方法的实例包括常规已知的方法,例如Southern印迹、PCR、DNA微阵列和测序分析。FGFR3蛋白质突变的检测方法的实例包括常规已知的方法,例如使用与FGFR3突变特异性结合的抗体的方法(ELISA、Western印迹、免疫染色等)和质谱分析。作为与FGFR3突变特异性结合的抗体,可以使用市售产品。另外可选地,抗体可以通过常规已知的方法生产。
在本发明中,术语“样品”不仅包括生物样品(例如,细胞、组织、器官、体液(血液、淋巴液等)、消化液、尿液),还包括核酸提取物(例如,基因组DNA提取物、mRNA提取物、cDNA制备物和由mRNA提取物制备的cDNA制备物等)和由这些生物样品获得的蛋白质提取物。另外,也可以对样品进行福尔马林固定处理、酒精固定处理、冷冻处理或石蜡包埋处理。作为生物样品,可以使用从活体获得的样品。根据生物样品的类型,可以选择获得生物样品的方法。
在本发明中,化合物1或其药学上可接受的盐可以直接作为治疗软骨发育异常的药剂使用;或者化合物1或其药学上可接受的盐与药用载体结合作为药物组合物使用。因此,在一实施方式中,本发明提供含有化合物1或其药学上可接受的盐的药物组合物。
当化合物1或其药学上可接受的盐作为活性成分掺入制剂中时,可以任选地加入药用载体,从而根据预防和治疗的目的形成合适的剂型。剂型的实例包括口服制剂、注射剂、栓剂、软膏剂、贴剂等。其中,优选口服制剂。口服制剂的实例包括片剂、胶囊剂、颗粒剂、散剂、糖浆剂等,没有任何限制。这些剂型可以通过本领域技术人员常规已知的方法形成。根据剂型,可以任选地将合适的载体,例如赋形剂、稀释剂、填充剂(bulking agent)或崩解剂添加到制剂或药物组合物中。
上述各剂量单位形式中的化合物1或其药学上可接受的盐的量取决于要施用化合物1或其盐的患者的状况、剂型等。通常,在口服制剂、注射剂和栓剂的情况下,每单位剂型(dosage unit form)的量分别优选为0.05~1000mg、0.01~500mg和1~1000mg。
化合物1或其药学上可接受的盐的每日剂量取决于患者的状况、体重、年龄、性别等,不能一概而论。例如,化合物1或其药学上可接受的盐用于成人(体重:60kg)每日的剂量通常为约1~1000mg,优选约10~500mg,更优选约10~300mg。
当施用化合物1或其药学上可接受的盐每天给药时,化合物1或其药学上可接受的盐的每日剂量为,例如,约1~200mg,优选2~100mg,更优选4~50mg,进一步更优选10~40mg。
当化合物1或其药学上可接受的盐间歇给药时,化合物1或其药学上可接受的盐的每日剂量为,例如,约2~1000mg,优选10~500mg,更优选20~200mg,进一步更优选50~160mg。
关于给药方案,化合物1或其药学上可接受的盐可以每天或间歇给药。
在本说明书中,“每天给药”可以是基于每天给药进行21天(一个周期)为周期的给药方案,并且可以在每个周期结束时提供休药期。
在本说明书中,“间歇给药”没有特别限定,只要满足至少每周2次、给药之间的给药间隔至少1天(某个给药日与下一个给药日之间的天数)的条件即可。
实例包括基于1周周期的给药方案,其中化合物1或其药学上可接受的盐每个周期每1~3天至少给药两次(某个给药日与下一个给药日之间有1~3天的给药间隔),该周期进行一次或重复两次以上;基于14天周期的给药方案,其中化合物1或其药学上可接受的盐给药4~7次,某个给药日与下一个给药日之间有1~3天的给药间隔,该周期进行一次或重复两次以上;基于14天周期的给药方案,其中在一个周期的14天中,化合物1或其药学上可接受的盐在第1天、第4天、第8天和第11天给药;基于14天周期的给药方案,其中在一个周期的14天中,化合物1或其药学上可接受的盐在第1天、第3天、第5天、第7天、第9天、第11天和第13天给药;以及基于14天周期的给药方案,其中在一个周期的14天中,化合物1或其药学上可接受的盐在第1天、第3天、第5天、第8天、第10天和第12天给药。在本发明中,“某个给药日与下一个给药日之间有X天的给药间隔”是指如果在第n天给药,则下一个给药日为第n+(1+X)天。例如,某个给药日与下一个给药日之间有1天的间隔是指在第1天进行给药时,在第3天进行下一次给药。
本发明还提供一种治疗软骨发育异常的方法,包括将有效量的化合物1或其药学上可接受的盐施用于软骨发育异常患者的步骤。化合物1或其药学上可接受的盐、其给药方法等如上所述。患者的实例包括人类、非人类哺乳动物等。非人类哺乳动物的实例包括猴、狗、猫、兔、小鼠、大鼠、豚鼠等。此外,如上所述,软骨发育异常的实例包括FGFR3突变软骨发育异常等。
因此,在一实施方式中,本发明提供一种治疗FGFR3突变软骨发育异常的方法,包括以下步骤(1)和(2):
(1)从患者来源的样品中检测FGFR3蛋白质或FGFR3基因的突变;和
(2)将有效量的化合物1或其药学上可接受的盐施用于以上步骤(1)中检测到FGFR3蛋白质或FGFR3基因的突变的患者。
在一实施方式中,本发明还提供以下方法:
一种治疗FGFR3突变软骨发育异常的方法,包括将有效量的化合物1或其药学上可接受的盐施用于具有FGFR3蛋白质或FGFR3基因的突变的患者,其中FGFR3蛋白质或FGFR3基因的突变从患者来源的样品中检出。
在上述治疗方法中,预期施用有效量的化合物1或其药学上可接受的盐的化学疗法对检出FGFR3蛋白质或FGFR3基因的突变的患者具有足够的治疗效果。在此,“治疗效果”可以通过骨延伸效果来评价。治疗效果也可以通过FGFR3功能抑制活性的程度(例如,抑制活性,以FGFR3磷酸化为指标)来估计。
实施例
以下结合实施例对本发明进行详细说明;然而,本发明不限于此。以下通过实施例对本发明进行全面描述;然而,可以理解,本领域技术人员可以进行各种改变和修改。因此,只要不脱离本发明的范围,这样的改变和修改都包括在本发明中。
实施例1:评价化合物1对FGFR3突变体的体外抑制活性
1-1构建FGFR3突变体表达载体
使用购自ORIGENE的FGFR3(NM_000142)Human Tagged ORF Clone(FGFR3野生型(WT)表达载体)作为FGFR3载体。使用上述载体作为模板构建用于表达各个突变体(G380R、N540K和K650E)的载体。
1-2以FGFR3磷酸化为指标测定FGFR3的抑制活性
在含有10%胎牛血清的DMEM中培养人胚肾细胞(HEK293T)。通过常规方法收集细胞后,将细胞悬浮在含有10%胎牛血清的DMEM中。根据使用Lipofectamine 3000试剂(Thermo Fisher Scientific)的脂质转染法,将上述FGFR3野生型载体或FGFR3突变体表达载体分别转染到细胞中。然后将细胞以每孔1.5×104个细胞/100μL接种在96孔板中。
准备溶媒(DMSO)组和化合物1的稀释系列(稀释系列有9个浓度,包括作为最大终浓度的3000nM,1000、300、100、30、10、3、1、0.3nM)作为药物溶液。将接种的细胞在37℃、5%CO2下孵育24小时,然后向其中加入11μL含有药物溶液的培养基,然后再孵育1小时。
使用人Phospho-FGFR3 DuoSet IC ELISA(R&D Systems)测定和评价FGFR3自身磷酸化能力的功能抑制作用。具体而言,将蛋白酶抑制剂(Roche)和磷酸酶抑制剂(Roche)添加到试剂盒附带的细胞裂解缓冲液中,并使用它们裂解细胞。根据试剂盒使用说明进行实验。使用酶标仪(Spectra MAX384,Molecular Devices)对每个孔进行比色定量。以对照组为100%,按照下式计算药物添加孔中的相对FGFR3磷酸化百分比。实验一式两份进行(每个处理组两个孔),并且使用两个孔的数据的平均值用于分析。
相对FGFR3磷酸化百分比(%)=(药物添加孔信号量)/(对照组信号量)×100
计算IC50值(50%抑制浓度)作为相对于对照组达到50%抑制作用时的浓度。
在FGFR3野生型(WT)或突变体(G380R、N540K或K650E)单独表达的293T细胞系中,化合物1显示出以下抑制活性(表1)。
表1
FGFR3 | FGFR3磷酸化抑制IC<sub>50</sub>(nM) |
WT | 3.2 |
G380R | 6.1 |
N540K | 19.8 |
K650E | 7.4 |
实施例2:使用软骨发育不全模型小鼠评价化合物1的骨延伸效果
使用FGFR3 ACH小鼠(Naski,M.C.et al.,Development,1998,125(24):4977-88;以下简称为ACH小鼠)。对FVB系ACH小鼠实施人工授精繁殖出大量F1杂交小鼠。然后提取基因组DNA,并通过PCR法确定基因类型。将化合物1溶于0.5%HPMC中制备得到不同浓度的溶液。根据给药日的个体体重,将各溶液以10mL/kg给药,使得化合物1的剂量为0.1mg/kg、1mg/kg或3mg/kg。将小鼠分为化合物1给药组和对照组(溶媒=0.5%HPMC给药)(WT和溶媒给药组:n=5;化合物1给药组:n=6),在21天~42天龄的小鼠上进行腹腔注射,1天1次每周5天(5天注射,2天休息)。对43天龄的小鼠实施安乐死,进行体重测量,通过X射线拍摄进行骨骼(股骨、胫骨和尺骨)长度测量。使用Faxitron X-Ray DX-50(AcroBio Corporation)进行X射线拍摄,用Image J进行测量。为了检验显著性,进行Dunnett多重比较检验。在图1至图5中,*表示p<0.05,**表示p<0.01,***表示p<0.001。
如图1至图5所示,在测定时(43天龄),与溶媒给药组相比,在化合物1给药组中观察到依赖于浓度的骨延伸效果。
随后,在给药后从小鼠中分离股骨。然后将软骨生长板用番红O染色,并测量其长度。结果如图4所示。ACH小鼠的生长板的平均宽度为148.3。在将化合物1施用于ACH小鼠的组中,平均宽度为206.4。与溶媒给药组相比,在化合物1给药组中确认有伸长。
实施例3:使用软骨发育不全模型小鼠评价化合物1的骨延伸效果
使用与实施例2相同的方法,改变化合物1的剂量(雄性小鼠:1mg/kg、3mg/kg或10mg/kg;雌性小鼠:1mg/kg、3mg/kg或6mg/kg),使用雄性和雌性小鼠(n=10)评价骨延伸效果。为了检验显著性,进行Dunnett的多重比较检验。在图6至图11中,*表示p<0.05,**表示p<0.01,***表示p<0.001,****表示p<0.0001。
如图6至图11所示,在测定时(43天龄),与溶媒给药组相比,化合物1给药组中观察到依赖于浓度的骨延伸效果。
实施例4:在疾病iPS细胞模型中评价药效
iPS细胞系由致死性发育异常I型(TD1,R248C)和软骨无形性症(ACH,G380A)患者的真皮成纤维细胞以及健康个体的真皮成纤维细胞构建,并诱导它们分化为软骨细胞。软骨组织由健康iPS细胞形成,而在从TD1-iPS细胞诱导的组织和从ACH-iPS细胞诱导的组织中,软骨成分减少(Yamashita et al.,Nature,2014,513(7519):507-11)。
在分化诱导系统中,从分化诱导开始后的第3天起,每次更换培养基(每2~7天更换一次培养基)时,添加1nM的化合物1,在分化诱导的第10周进行分析。使用瑞舒伐他汀(Rosuvastatin)作为阳性对照。作为评价项目,使用组织切片染色(番红染色)和COL2A1和Aggrecan(ACAN)的mRNA表达作为指标。为了检验显著性,进行非配对检验。在图13中,*表示p<0.05。
如图12所示,通过添加化合物1,观察到作为软骨细胞外基质的构成成分的葡糖胺聚糖被染色的阳性番红染色图像。
此外,如图13所示,与未添加化合物1的细胞相比,添加了化合物1的细胞中COL2A1和ACAN的mRNA表达增加。
序列表
<110> 国立大学法人京都大学
大鹏药品工业株式会社
<120> 软骨营养不良的治疗
<130> P20-312WO
<150> JP 2020-014260
<151> 2020-01-31
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Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ala Leu Phe Asp Arg Val
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Tyr Thr His Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu
675 680 685
Ile Phe Thr Leu Gly Gly Ser Pro Tyr Pro Gly Ile Pro Val Glu Glu
690 695 700
Leu Phe Lys Leu Leu Lys Glu Gly His Arg Met Asp Lys Pro Ala Asn
705 710 715 720
Cys Thr His Asp Leu Tyr Met Ile Met Arg Glu Cys Trp His Ala Ala
725 730 735
Pro Ser Gln Arg Pro Thr Phe Lys Gln Leu Val Glu Asp Leu Asp Arg
740 745 750
Val Leu Thr Val Thr Ser Thr Asp Glu Tyr Leu Asp Leu Ser Ala Pro
755 760 765
Phe Glu Gln Tyr Ser Pro Gly Gly Gln Asp Thr Pro Ser Ser Ser Ser
770 775 780
Ser Gly Asp Asp Ser Val Phe Ala His Asp Leu Leu Pro Pro Ala Pro
785 790 795 800
Pro Ser Ser Gly Gly Ser Arg Thr
805
Claims (17)
1.一种用于治疗软骨发育异常的药物组合物,包括1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐。
2.根据权利要求1所述的药物组合物,其中所述软骨发育异常是软骨发育不全、软骨发育不良或致死性发育异常。
3.根据权利要求1或2所述的药物组合物,其中所述软骨发育异常是软骨发育不全。
4.根据权利要求1-3中任一项所述的药物组合物,其中所述软骨发育异常是具有FGFR3突变的软骨发育异常。
5.根据权利要求4所述的药物组合物,其中所述FGFR3突变是FGFR3中第248位精氨酸、第380位甘氨酸、第540位天冬酰胺或第650位赖氨酸的突变。
6.根据权利要求4所述的药物组合物,其中所述具有FGFR3突变的软骨发育异常是具有FGFR3突变的软骨发育不全。
7.根据权利要求6所述的药物组合物,其中所述软骨发育不全是具有FGFR3中的第380位甘氨酸突变为精氨酸的FGFR3突变的软骨发育不全。
8.根据权利要求4所述的药物组合物,其中所述具有FGFR3突变的软骨发育异常是具有FGFR3突变的软骨发育不良。
9.根据权利要求8所述的药物组合物,其中所述软骨发育不良是具有FGFR3中的第540位天冬酰胺突变为赖氨酸的FGFR3突变的软骨发育不良。
10.根据权利要求4所述的药物组合物,其中所述具有FGFR3突变的软骨发育异常是具有FGFR3突变的致死性发育异常。
11.根据权利要求10所述的药物组合物,其中所述致死性发育异常是具有FGFR3中的第248位精氨酸突变为半胱氨酸的FGFR3突变,或者FGFR3中的第650位赖氨酸突变为谷氨酸的FGFR3突变的致死性发育异常。
12.一种用于治疗软骨发育异常的药剂,包括1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐。
13.1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐,其用于治疗软骨发育异常。
14.1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐用于治疗软骨发育异常的用途。
15.1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐在制造用于治疗软骨发育异常的药物中的用途。
16.一种治疗软骨发育异常的方法,包括将有效量的1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐施用于软骨发育异常患者的步骤。
17.一种商业包装,包括作为活性成分的1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐,以及使用1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮或其药学上可接受的盐治疗受试者中的软骨发育异常的说明书。
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WO2015008844A1 (ja) * | 2013-07-18 | 2015-01-22 | 大鵬薬品工業株式会社 | Fgfr阻害剤耐性癌の治療薬 |
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