CN107427501A - 用于治疗癌症的联合方法 - Google Patents
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- CN107427501A CN107427501A CN201680011030.XA CN201680011030A CN107427501A CN 107427501 A CN107427501 A CN 107427501A CN 201680011030 A CN201680011030 A CN 201680011030A CN 107427501 A CN107427501 A CN 107427501A
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Abstract
提供了通过联合具有MDM2抑制活性的化合物和具有FLT3抑制活性的化合物获得的癌症治疗药物/方法。提供了通过联合(3'R,4'S,5'R)‑N‑[(3R,6S)‑6‑氨基甲酰基四氢‑2H‑吡喃‑3‑基]‑6"‑氯‑4'‑(2‑氯‑3‑氟吡啶‑4‑基)‑4,4‑二甲基‑2"‑氧代‑1",2"‑二氢二螺[环己烷‑1,2'‑吡咯烷‑3',3"‑吲哚]‑5'‑甲酰胺或其药学上可接受的盐和N‑(5‑叔丁基‑异噁唑‑3‑基)‑N'‑{4‑[7‑(2‑吗啉‑4‑基‑乙氧基)咪唑并[2,1‑b][1,3]苯并噻唑‑2‑基]苯基}脲或其药学上可接受的盐获得的药物或联合治疗方法。
Description
技术领域
本发明涉及包含具有鼠双微体2 (MDM2)抑制活性的化合物和具有Fms样酪氨酸激酶3 (FLT3)抑制活性的化合物的组合的用于治疗癌症的药物和方法。
背景技术
p53已知为抑制细胞的癌变的重要因子。p53是一种转录因子,其响应于各种应激而诱导参与细胞周期和细胞凋亡的基因的表达。p53被认为通过其转录调节功能来抑制细胞的癌变。事实上,在约一半的人癌症病例中观察到p53基因的缺失或突变。
同时,鼠双微体2 (MDM2)(一种E3泛素连接酶)的过表达已知为这样的细胞的癌变的因素,所述细胞尽管存在正常的p53,但仍发生癌变。MDM2是一种其表达由p53诱导的蛋白。MDM2通过如下来负调节p53:结合p53的转录活性结构域以降低p53的转录活性、从细胞核输出p53和通过充当针对p53的泛素连接酶来介导p53的降解。因此,认为在MDM2过表达的细胞中促进p53的功能失活和降解,导致癌变(非专利文献1)。
注意到此类MDM2的功能,已经使用抑制MDM2对p53功能的抑制的物质作为候选抗肿瘤剂来尝试许多方法。已经报道了靶向MDM2-p53结合位点的MDM2抑制剂的实例,其包括螺羟吲哚衍生物(专利文献1至15和非专利文献1至3)、吲哚衍生物(专利文献16)、吡咯烷-2-甲酰胺衍生物(专利文献17)、吡咯烷酮衍生物(专利文献18)、异吲哚啉酮衍生物(专利文献19和非专利文献4)和二螺吡咯烷化合物(专利文献20)。
FLT3是与KIT、FMS和PDGFR等一起属于受体酪氨酸激酶III类的蛋白,并且被认为参与造血系统(非专利文献5至8)。其结构具有由5个免疫球蛋白样结构域构成的细胞外区域,一个近膜区域(JM结构域),通过激酶插入结构域(KI结构域)分开的两个酪氨酸激酶结构域(TK1和TK2),和C-端结构域。FLT3在脑、胎盘、肝脏和造血干细胞中高度表达(非专利文献6至9)。
FLT3的配体(FL)在骨髓的基质细胞中表达,并且单独或与其他细胞因子协同刺激干细胞(非专利文献10至13)。FL和FLT3之间的配体-受体相互作用被认为在造血系统中具有重要功能。
同时,在大多数情况下,在急性骨髓性白血病(AML)或急性淋巴性白血病(ALL)患者的样品中观察到FLT3的高表达,并且在慢性骨髓性白血病(CML)中也看到FLT3的高表达。还已知,AML细胞的生长比通过FL的刺激的ALL细胞的生长更显著增强(非专利文献14至18)。FLT3基因是急性骨髓性白血病(AML)病例中最频繁突变的基因,并且在近膜区域中的内部串联重复(ITD)(非专利文献19)或FLT3活化环区域中的突变(非专利文献20)在约30%至35%的患者中得到证实。FLT3-ITD或活化环区域的突变与酪氨酸激酶活性的组成型活化相关。
已知具有FLT3抑制活性的N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲(奎扎替尼(quizartinib))具有抗肿瘤活性。已经在文献中提出使用奎扎替尼治疗各种癌症。已经报道了各种给药方案。参见,例如,专利文献21-23(其以其整体通过引用并入本文)。此外,已经报道了联合使用奎扎替尼和蒽环霉素、拓扑异构酶抑制剂或肿瘤细胞代谢拮抗剂的效果(专利文献24)。
关于MDM2抑制剂和FLT3抑制剂之间的关系,已经报道了对于其细胞含有具有活化突变的FLT3的患者,优选施用MDM2抑制剂(专利文献25)。该文献还指出,对于其细胞含有具有活化突变的FLT3的患者,优选FLT3抑制剂和MDM2抑制剂的联合施用,但其没有公开特定药物的联合使用的具体效果。
存在关于各种MDM2抑制剂和各种抗肿瘤剂的联合使用的效果的各种报道(专利文献26至29)。
引文列表
专利文献
专利文献1: WO2006/091646
专利文献2: WO2006/136606
专利文献3: WO2007/104664
专利文献4: WO2007/104714
专利文献5: WO2008/034736
专利文献6: WO2008/036168
专利文献7: WO2008/055812
专利文献8: WO2008/141917
专利文献9: WO2008/141975
专利文献10: WO2009/077357
专利文献11: WO2009/080488
专利文献12: WO2010/084097
专利文献13: WO2010/091979
专利文献14: WO2010/094622
专利文献15: WO2010/121995
专利文献16: WO2008/119741
专利文献17: WO2010/031713
专利文献18: WO2010/028862
专利文献19: WO2006/024837
专利文献20: WO2012/121361
专利文献21: 美国专利申请公开US 2007/0232604
专利文献22: 美国专利申请公开US 2009/0123418
专利文献23: 美国专利申请公开US 2009/0131426
专利文献24: WO2010/111172
专利文献25: WO2011/127058
专利文献26: EP1712235
专利文献27: WO2007/115289
专利文献28: WO2013/139724
专利文献29: WO2014/107713
非专利文献
非专利文献1: J.Am.Chem.Soc., 2005, 127, 10130-10131
非专利文献2: J.Med.Chem., 2006, 49, 3432-3435
非专利文献3: J.Med.Chem., 2009, 52, 7970-7973
非专利文献4: J.Med.Chem., 2006, 49, 6209-6221
非专利文献5: Genomics,1991, 19, 380-385
非专利文献6: Oncogene, 1991, 6, 1641-1650
非专利文献7: Cell, 1991, 65, 1143-1152
非专利文献8: Blood, 1993, 82, 1110-1119
非专利文献9: Blood, 1996, 87, 1317-1325
非专利文献10: Nature, 1994, 368, 643-648
非专利文献11: Blood, 1995, 86, 3413-3420
非专利文献12: Blood, 1995, 85, 1762-1768
非专利文献13: Leukemia, 1996, 10, 1012-1018
非专利文献14: Blood, 1995, 86, 4105-4114
非专利文献15: Leukemia, 1996, 10, 1584-1591
非专利文献16: Blood, 1996, 88, 3987-3997
非专利文献17: Blood, 1992, 80, 2584-2593
非专利文献18: Leukemia, 1996, 10, 261-270
非专利文献19: Leukemia, 1996, 10, 1911-1918
非专利文献20: Blood, 2001, 97 2434-2439。
发明概述
技术问题
本发明的目的是提供包含具有MDM2抑制活性的化合物和具有FLT3抑制活性的化合物的组合的用于治疗癌症的药物和方法。
问题的解决方案
作为广泛研究的结果,本发明人已经发现联合使用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺(其为具有MDM2抑制活性的化合物)或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲(其为具有FLT3抑制活性的化合物)或药学上可接受的盐尤其产生优异的抗肿瘤效果,同时保持低不良反应(例如体重减轻),并且完成了本发明。
具体地,本发明涉及以下[1]至[21]:
[1]用于癌症治疗的药物,其包含联合施用的(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐。
[2]根据权利要求1所述的药物,其中(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐分别作为活性成分包含在不同的制剂中并且同时或不同时间施用。
[3]根据权利要求1所述的药物,其中(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐包含在单一制剂中。
[4]根据权利要求1所述的药物,其中所述药物是包含(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的药盒制剂。
[5]用于治疗癌症的方法,其包括联合施用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐。
[6]根据权利要求1至4中任一项所述的药物,其中所述化合物的各自盐是(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺对甲苯磺酸盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲二盐酸盐。
[7]根据权利要求5所述的治疗方法,其中所述化合物的各自盐是(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺对甲苯磺酸盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲二盐酸盐。
[8]根据权利要求1至4和6中任一项所述的药物,其中所述癌症是血癌(白血病、淋巴瘤或多发性骨髓瘤)、脑肿瘤、头颈癌、食管癌、胃癌、阑尾癌、结肠癌、肛门癌、胆囊癌、胆管癌、胰腺癌、胃肠道间质瘤、肺癌、肝癌、间皮瘤、甲状腺癌、肾癌、前列腺癌、神经内分泌肿瘤、黑色素瘤、乳腺癌、子宫内膜癌、子宫颈癌、卵巢癌、骨肉瘤、软组织肉瘤、卡波西肉瘤、肌肉瘤、肾癌、膀胱癌或睾丸癌。
[9]根据权利要求5或7所述的治疗方法,其中所述癌症是血癌(白血病、淋巴瘤或多发性骨髓瘤)、脑肿瘤、头颈癌、食管癌、胃癌、阑尾癌、结肠癌、肛门癌、胆囊癌、胆管癌、胰腺癌、胃肠道间质瘤、肺癌、肝癌、间皮瘤、甲状腺癌、肾癌、前列腺癌、神经内分泌肿瘤、黑色素瘤、乳腺癌、子宫内膜癌、子宫颈癌、卵巢癌、骨肉瘤、软组织肉瘤、卡波西肉瘤、肌肉瘤、肾癌、膀胱癌或睾丸癌。
[10] 根据权利要求1至4和6中任一项所述的药物,其中所述癌症是白血病。
[11] 根据权利要求5或7所述的治疗方法,其中所述癌症是白血病。
[12] 根据权利要求1至4和6中任一项所述的药物,其中所述癌症是具有FLT3的活化突变的白血病。
[13] 根据权利要求5或7所述的治疗方法,其中所述癌症是具有FLT3的活化突变的白血病。
[14] 根据权利要求1至4和6中任一项所述的药物,其中所述癌症是急性骨髓性白血病(AML)。
[15] 根据权利要求5或7所述的治疗方法,其中所述癌症是急性骨髓性白血病(AML)。
[16] 根据权利要求1至4和6中任一项所述的药物,其中所述癌症是具有FLT3-ITD突变的急性骨髓性白血病(AML)。
[17] 根据权利要求5或7所述的治疗方法,其中所述癌症是具有FLT3-ITD突变的急性骨髓性白血病(AML)。
[18] 根据权利要求1至4和6中任一项所述的药物,其中所述癌症具有野生型TP53。
[19] 根据权利要求5或7所述的治疗方法,其中所述癌症是具有野生型TP53的癌症。
[20] 根据权利要求1至4和6中任一项所述的药物,其中所述癌症是使用基因签名证实为MDM2抑制剂敏感的癌症。
[21] 根据权利要求5或7所述的治疗方法,其中所述癌症使用基因签名证实为MDM2抑制剂敏感的。
本发明的有利效果
本发明可用作治疗癌症的方法和/或抗癌剂。
附图简述
[图1-1] 图1-1是显示(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺甲苯磺酸盐(化合物A)和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲(奎扎替尼)的联合使用对小鼠中皮下移植的具有FLT3-ITD突变和野生型TP53的人急性骨髓性白血病细胞系MOLM-13的肿瘤的体内效果和由其联合施用引起的体重变化的图。符号×描绘未处理的对照组,符号空心圆描绘0.5 mg/kg奎扎替尼,符号实心圆描绘1 mg/kg奎扎替尼,符号空心三角形描绘25 mg/kg化合物A,符号空心正方形描绘25 mg/kg化合物A + 0.5 mg/kg奎扎替尼,且符号实心正方形描绘25 mg/kg化合物A + 1 mg/kg奎扎替尼。横轴显示肿瘤接种后的天数。上小图的纵轴显示从肿瘤大小计算的估计的肿瘤体积。下小图的纵轴显示在施用的第一天相对于体重的体重变化%。横轴上的符号实心三角形描绘每种化合物的施用日。误差条代表上小图的SE和下小图的SD。
[图1-2] 图1-2是显示(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺甲苯磺酸盐(化合物A)和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲(奎扎替尼)的联合使用对小鼠中皮下移植的具有FLT3-ITD突变和野生型TP53的人急性骨髓性白血病细胞系MOLM-13的肿瘤的体内效果和由其联合施用引起的体重变化的图。符号×描绘未处理的对照组,符号空心圆描绘0.5 mg/kg奎扎替尼,符号实心圆描绘1 mg/kg奎扎替尼,符号实心三角形描绘50 mg/kg化合物A,符号空心正方形描绘50 mg/kg化合物A + 0.5 mg/kg奎扎替尼,且符号实心正方形描绘50 mg/kg化合物A + 1 mg/kg奎扎替尼。横坐标显示肿瘤接种后的天数。上小图的纵坐标显示从肿瘤大小计算的估计的肿瘤体积。下小图的纵坐标显示在施用的第一天相对于体重的体重变化%。横坐标上的符号实心三角形描绘每种化合物的施用日。误差条代表上小图的SE和下小图的SD。
实施方案的描述
在本发明中,(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺是WO2012/121361中的实施例70的化合物。该化合物可以通过WO2012/121361中描述的方法产生(WO2012/121361以其整体通过引用并入本文)。
在本发明中,N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲也称为1-(5-叔丁基-1,2-噁唑-3-基)-3-(4-{7-[2-(吗啉-4-基)乙氧基]咪唑并[2,1-b][1,3]苯并噻唑-2-基}苯基)脲或也称为奎扎替尼或AC220。该化合物由下式代表:
[式1]
该化合物可以通过WO2007/109120中描述的方法产生(WO2007/109120以其整体通过引用并入本文)。
在本发明中,(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲可以是各种药学上可接受的盐。
盐的实例可以包括:氢卤化物诸如盐酸盐和氢碘酸盐;无机酸盐诸如硝酸盐、高氯酸盐、硫酸盐和磷酸盐;低级烷烃磺酸盐诸如甲磺酸盐、三氟甲磺酸盐和乙磺酸盐;芳基磺酸盐诸如苯磺酸盐和对甲苯磺酸盐;有机酸盐诸如甲酸盐、乙酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐和马来酸盐;氨基酸盐诸如鸟氨酸盐、谷氨酸盐和天冬氨酸盐;碱金属盐诸如钠盐、钾盐和锂盐;碱土金属盐诸如钙盐和镁盐;无机盐诸如铵盐;和有机胺盐诸如二苄胺盐、吗啉盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、二乙胺盐、三乙胺盐、环己胺盐、二环己胺盐、N,N'-二苄基乙二胺盐、二乙醇胺盐、N-苄基-N-(2-苯基乙氧基)胺盐、哌嗪盐、四甲基铵盐和三(羟甲基)甲胺盐。
(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺的盐优选为对甲苯磺酸盐。N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲的盐优选为盐酸盐,特别是二盐酸盐。
在本发明中,(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐可以各自以游离或溶剂合物形式存在。由本发明的通式(1)代表的化合物或其盐可以例如通过吸收空气中的水分而以水合物形式存在。溶剂合物没有特别限制,只要其是药学上可接受的。具体地,溶剂合物优选为水合物、乙醇溶剂合物等。此外,由通式(1)代表的化合物当含有氮原子时可以呈N-氧化物形式。这些溶剂合物和N-氧化物形式也包括在本发明中。
(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐可以根据其结构而具有立体异构体。该化合物或盐也涵盖所有这些立体异构体和这些立体异构体的任何比率的混合物。立体异构体如1996 IUPC, Pure and Applied Chemistry 68, 2193-2222中所定义。当(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐各自作为互变异构体存在时,这些互变异构体可以平衡存在,或者某一形式可以主要存在。所有这些情况都包括在本发明的范围内。互变异构体是指由分子的一个原子的质子转移至另一个原子而导致的异构体。
(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐可以各自为“药学上可接受的前药化合物”,其通过酶促氧化、还原、水解等或通过由胃酸等诱导的水解等(由于在体内在生理条件下由酶、胃酸等诱导的反应)转化为所需化合物。
前药的实例包括通过酰化、烷基化或磷酸化获得的化合物。
化合物的前药可以根据本领域已知的方法由化合物(1)产生。此外,化合物的前药还包括在生理条件下转化为所需化合物的那些,如"Development of PharmaceuticalProducts", vol. 7, Molecule Design, p. 163-198, Hirokawa-Shoten Ltd. (1990)中所述。
在本发明中,术语“肿瘤”和“癌症”可互换使用。此外,在本发明中,肿瘤、恶性肿瘤、癌症、恶性赘生物、癌、肉瘤等可以统称为“肿瘤”或“癌症”。
在本发明中,“FLT3”意指Fms样酪氨酸激酶3 (FLT3),并且具有与FLK2、STK1、CD135和FLK-2相同的含义。FLT3还包括从各种动物物种衍生的同系物。人FLT3是在NCBI中以RefSEQ: 登录号NM_004119.2 (蛋白: RefSeq NP_004110.2)登记的分子。
FLT3 mRNA具有如下给出的序列。然而,应当理解,甚至没有突变的FLT3由于多态性等而在个体间的序列上可以不同。
FLT3蛋白具有如下所述的氨基酸序列。然而,应当理解,甚至没有突变的FLT3由于多态性等而在个体间的序列上可以不同。
在本发明中,“FLT3的活化突变”意指引起FLT3的配体非依赖性活化的突变。其实例包括但不具体限于近膜区域(JM区域)中的内部串联重复(ITD),以及在FLT3的活化环区中存在的点突变D835V、D835E、D835N、D835Y和D835H。FLT3-ITD突变主要存在于JM区域的外显子14中,并且也发现于外显子15中。
在本发明中,“野生型TP53”意味着编码p53蛋白的基因TP53是具有在NCBI中以RefSEQ: 登录号NM_000546 (蛋白: RefSeq NP_000537)登记的序列的基因。
野生型TP53 mRNA具有以下给出的序列。然而,应当理解,甚至没有突变的TP53由于多态性等而在个体间的序列上可以不同。
TP53蛋白具有如下所述的氨基酸序列。然而,应当理解,甚至没有突变的TP53由于多态性等而在个体间的序列上可以不同。
在本发明中,“基因签名”意指由多个基因组成的单一基因或基因群组(genegroup),所述多个基因的表达模式的特征在于生物表型或医学病况,诸如特定疾病的发病率,对特定药物的反应,或特定疾病的预后。
在本发明中,“生物样品”是指从个体分离的组织、液体或细胞,或其混合物。其实例可以包括但不限于肿瘤活检样品、脊髓液、胸膜液、腹内液、淋巴、皮肤切片、血液、尿液、排泄物、痰液、呼吸器官、肠道、泌尿生殖道、唾液、乳、消化器官和由其收集的细胞。“生物样品”的优选实例可以包括在为了治疗癌症疾病目的而进行的手术期间获得的测试主体衍生的切除组织的一部分,通过活检等从怀疑具有癌症疾病的测试主体收集的组织的一部分,和衍生自胸膜液或腹内液的细胞。
生物样品可以是由从个体分离的组织、液体或细胞制备的蛋白提取物或核酸提取物或其混合物等。蛋白提取物或核酸提取物可以通过使用本领域本身已知的蛋白制备方法或核酸制备方法来制备。
本发明的一个方面涉及癌症治疗的药物,其包含联合施用的(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐。
在本发明中,包含“联合施用的”(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的“药物”是基于联合施用两种药物的假设的药物。
在本发明中,(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的“联合施用”意味着在给定时段内将两种药物并入受体体内。可以施用在单一制剂中含有两种药物的制剂,或者药物可以制备成分开的制剂并分开施用。在制备分开制剂的情况下,其施用时机没有特别限制。分开的制剂可以同时施用或可以在不同时间或不同日以交错方式施用。在不同时间或不同日施用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的情况下,其施用顺序没有特别限制。通常,这些制剂根据其各自施用方法进行施用。因此,这些制剂可以以相同数量的剂量施用,或者可以以不同数量的剂量施用。此外,在制备分开制剂的情况下,制剂的各自施用方法(施用途径)可以彼此相同,或者这些制剂可以通过不同的施用方法(施用途径)施用。两种药物不必在体内同时存在,并且可以经给定时段(例如1个月,优选1周,更优选几天,甚至更优选1天)并入体内。活性成分之一在施用其他活性成分时可能已经在体内消失。
本发明的药物的剂型的实例包括1)施用包含(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的单一制剂,2)通过相同的施用途径同时施用分别由(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐制备的两种制剂,3)通过相同的施用途径以交错方式施用分别由(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐制备的两种制剂,4)通过不同的施用途径同时施用分别由(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐制备的两种制剂,和5)通过不同的施用途径以交错方式施用分别由(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐制备的两种制剂。
在本发明中,两种不同的制剂可以呈包含这些制剂的药剂盒的形式。
根据本发明的药物可以含有(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和/或N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐和药学上可接受的载体,并且可以作为各种注射剂诸如静脉内注射剂、肌内注射剂和皮下注射剂或通过各种方法诸如口服施用或经皮施用来施用。药学上可接受的载体意指参与本发明的化合物或含有本发明的化合物的组合物从一个给定器官转运至另一个器官的药学上可接受的材料(例如,赋形剂、稀释剂、添加剂和溶剂)。
可以通过根据施用方法选择合适的制剂形式(例如口服制剂或注射剂)和使用常规用于制备制剂的各种方法来制备制剂。口服制剂的实例可以包括片剂、粉剂、颗粒剂、胶囊剂、丸剂、锭剂、溶液剂、糖浆剂、酏剂、乳剂和油性或水性悬剂。在口服施用中,可以使用游离化合物或盐形式。可以通过与药学上可接受的酸形成酸加合物或通过形成碱金属盐诸如钠盐来制备水性制剂。作为注射剂,可以在制剂中使用稳定剂、防腐剂、溶解助剂等。在容器中填充可以含有这些助剂等的溶液后,用于使用的制剂可以通过冻干等制备为固体制剂。此外,可以在一个容器中填充一个剂量,或者可以在容器中填充两个或更多个剂量。
固体制剂的实例包括片剂、粉剂、颗粒剂、胶囊剂、丸剂和锭剂。这些固体制剂可以含有药学上可接受的添加剂连同本发明的化合物。添加剂的实例包括填料、填充剂、粘合剂、崩解剂、溶解促进剂、皮肤润湿剂和润滑剂。可以根据需要选择和混合这些添加剂以制备制剂。
液体制剂的实例包括溶液剂、糖浆剂、酏剂、乳剂和悬剂。添加剂的实例包括悬浮剂和乳化剂。可以根据需要选择和混合这些添加剂以制备制剂。
药物材料的实例可包括但不限于:氨基酸诸如甘氨酸、丙氨酸、谷氨酰胺、天冬酰胺、精氨酸和赖氨酸;抗微生物剂;抗氧化剂诸如抗坏血酸、硫酸钠和亚硫酸氢钠;缓冲剂诸如磷酸盐、柠檬酸盐或硼酸盐缓冲剂、碳酸氢钠和Tris-HCl溶液;填料诸如甘露醇和甘氨酸;螯合剂诸如乙二胺四乙酸(EDTA);络合剂诸如咖啡因、聚乙烯吡咯烷酮(polyvinylpyrrolidine)、β-环糊精和羟丙基-β-环糊精;疏松剂诸如葡萄糖、甘露糖和糊精;其他碳水化合物诸如单糖和二糖;着色剂;矫味剂;稀释剂;乳化剂;亲水性聚合物诸如聚乙烯吡咯烷酮;低分子量多肽;盐形成抗衡离子;防腐剂如苯扎氯铵、苯甲酸、水杨酸、硫柳汞、苯乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯己定、山梨酸和过氧化氢;溶剂诸如甘油、丙二醇和聚乙二醇;糖醇诸如甘露醇和山梨醇;悬浮剂;表面活性剂诸如脱水山梨糖醇酯、聚山梨醇酯诸如聚山梨醇酯20和聚山梨醇酯80、triton、氨丁三醇、卵磷脂和胆固醇;稳定性增强剂诸如蔗糖和山梨醇;弹性增强剂(elasticity enhancers)诸如氯化钠、氯化钾、甘露醇和山梨醇;转运剂;赋形剂;和/或药物添加剂。添加的这些药物材料的量优选为药物重量的0.01至100倍,特别是0.1至10倍。制剂中优选的药物组合物的配方可以由本领域技术人员根据适用的疾病、适用的给药途径等适当地确定。
药物组合物中的赋形剂或载体可以是液体或固体。合适的赋形剂或载体可以是通常用于可注射水、生理盐水、人工脑脊液和肠胃外施用中的其他材料。中性生理盐水或含有血清白蛋白的生理盐水可以用作载体。药物组合物可以含有pH 7.0-8.5的Tris缓冲液,pH4.0-5.5的乙酸盐缓冲液或pH 3.0-6.2的柠檬酸盐缓冲液。这些缓冲液也可以含有山梨醇或其他化合物。
N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的制剂的优选实例包括WO2014/055397中描述的制剂(WO2014/055397以其整体通过引用并入本文)。
本发明的药物可用于哺乳动物、特别是人的癌症治疗中。根据医师的判断,本发明的药物的剂量和施用间隔可以根据疾病的部位、患者的身高、体重、性别或病史适当地选择。当将本发明的药物施用于人时,就一种类型的活性成分而言,剂量范围为每天约0.01至500 mg/kg体重,优选约0.1至100 mg/kg体重。优选地,将本发明的活性成分每天一次施用于人,或者将剂量分成两至四次,并且以适当间隔重复施用。此外,如果需要,根据医师的判断,每日剂量可以超过上述剂量。
对于N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的施用方法的实例,参见WO2009/061446中描述的方法、WO2010/132787中描述的方法和US8357690中描述的方法,其全部以其整体通过引用并入本文。该活性成分可以每天一次施用1周、2周、3周、4周或5周。其优选的实例包括连续施用12至450 mg、例如20 mg、30 mg、40 mg、50 mg、60 mg、90 mg、135 mg、200 mg、300 mg或450 mg该药剂28天的方法,连续施用上述剂量连同额外抗癌剂8至21天的方法,和连续施用上述剂量连同额外抗癌剂4至17天的方法。
待治疗的癌症的类型没有特别限制,只要证实癌症对于通过本发明的联合使用的治疗是敏感的。其实例包括血癌(白血病、淋巴瘤或多发性骨髓瘤)、脑肿瘤、头颈癌、食管癌、胃癌、阑尾癌、结肠癌、肛门癌、胆囊癌、胆管癌、胰腺癌、胃肠道间质瘤、肺癌、肝癌、间皮瘤、甲状腺癌、肾癌、前列腺癌、神经内分泌肿瘤、黑色素瘤、乳腺癌、子宫内膜癌、子宫颈癌、卵巢癌、骨肉瘤、软组织肉瘤、卡波西肉瘤、肌肉瘤、肾癌、膀胱癌和睾丸癌。其中,优选白血病,特别是急性骨髓性白血病(AML)。更优选具有FLT3的活化突变的白血病,特别优选具有FLT3-ITD突变的急性骨髓性白血病。
在本发明中,检测“FLT3的活化突变”的方法包括检测基因组DNA上的突变的方法,以及当基因组DNA上的突变反映为转录产物中的碱基变化或翻译产物中的氨基酸变化时,检测转录产物或翻译产物(即间接检测)中的该变化的方法,以及基于磷酸化的FLT3(因为FLT3的活化涉及磷酸化水平的升高)的检测的方法。
在一个优选的实施方案中,用于检测突变的方法包括直接测定测试主体衍生的生物样品中的基因区域的核苷酸序列以从而检测突变的方法。在本发明中,“FLT3基因区域”意指含有FLT3基因的基因组DNA上的给定区域。该区域还含有FLT3基因的表达控制区域(例如,启动子区域和增强子区域),FLT3基因的3'末端非翻译区域等。这些区域中的突变可以影响例如FLT3基因的转录活性。
在该方法中,首先,从测试主体衍生的生物样品制备DNA样品。DNA样品的实例包括基因组DNA样品和通过逆转录从RNA制备的cDNA样品。
用于从生物样品提取基因组DNA或RNA的方法没有特别限制,并且可以适当地选择本领域已知的方法用于使用。用于提取基因组DNA的方法的实例包括SDS苯酚方法(涉及使用蛋白水解酶(蛋白酶K)、表面活性剂(SDS)和苯酚将含有尿素的溶液或乙醇中保存的组织中的蛋白变性和通过使用乙醇从组织沉淀来提取DNA的方法)和使用Clean Columns(R)(由Nexttec Biotechnologie GmbH制造)、AquaPure(R) (由Bio-Rad Laboratories, Inc.制造)、ZR Plant/Seed DNA试剂盒(由Zymo Research Corp.制造)、Aqua GenomicSolution(R) (由MoBiTec GmbH制造)、prepGEM(R) (由ZyGEM NZ Ltd.制造)或BuccalQuick(R) (由TrimGen Corp.制造)的DNA提取方法。用于提取RNA的方法的实例包括使用苯酚和离液序列高的盐的提取方法(更具体地,使用市售试剂盒诸如TRIzol (由Invitrogen Corp.制造)或ISOGEN (由Wako Pure Chemical Industries, Ltd.制造)的提取方法),和使用其他市售试剂盒(RNAPrep总RNA提取试剂盒(由Beckman Coulter, Inc.制造)、RNeasy Mini (由Qiagen N.V.制造), RNA提取试剂盒(由Pharmacia Biotech Inc.制造),等)的方法。用于从提取的RNA制备cDNA的逆转录酶的实例包括但不具体限于衍生自逆转录病毒诸如RAV(Rous相关病毒)或AMV(禽成髓细胞瘤病毒)的逆转录酶,以及衍生自小鼠逆转录病毒诸如MMLV(莫洛尼鼠白血病病毒)的逆转录酶。
在该实施方案中,随后分离在FLT3基因区域中含有突变位点的DNA,并测定分离的DNA的核苷酸序列。DNA的分离可以通过例如使用设计成侧接FLT3基因区域中的突变的一对寡核苷酸引物和作为模板的基因组DNA或RNA的PCR来进行。分离的DNA的核苷酸序列的测定可以通过本领域技术人员通常已知的方法(诸如Maxam-Gilbert方法或Sanger方法)进行。
可以将测定的DNA或cDNA的核苷酸序列与对照(例如,衍生自相同测试主体的非癌组织的DNA或cDNA的核苷酸序列)进行比较,从而确定测试主体的癌细胞中的FLT3基因区域中的突变的存在或不存在。
除了直接测定DNA或cDNA的核苷酸序列的方法之外,还可以通过能够检测突变的各种方法来进行用于检测FLT3基因区域中的突变的方法。
例如,在所述方法之一中,首先从生物样品制备DNA或cDNA样品。随后,制备具有与在FLT3基因区域中含有突变的核苷酸序列互补的核苷酸序列的报道荧光染料和猝灭剂荧光染料标记的寡核苷酸探针。然后,寡核苷酸探针与DNA样品杂交。然后,使用与寡核苷酸探针杂交的DNA样品作为模板,扩增在FLT3基因区域中含有突变的核苷酸序列。然后,检测由报道荧光染料通过与扩增相关的寡核苷酸探针的分解而发出的荧光。随后,将检测的荧光与对照进行比较。此方法的实例包括双染料探针法(double die probe method),所谓的TaqMan(R)探针法。
在替代方法中,从生物样品制备DNA或cDNA样品。随后,在含有嵌入剂的反应体系中,使用DNA样品作为模板,扩增在FLT3基因区域中含有突变的核苷酸序列,所述嵌入剂在插入DNA的两条链之间时会发射荧光。然后,改变反应体系的温度,并检测由嵌入剂发射的荧光强度的变化。将检测到的由温度改变引起的荧光强度的变化与对照进行比较。此方法的实例包括高分辨率熔解(HRM)方法。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。随后,扩增在FLT3基因区域中含有突变位点的DNA。然后,用限制性酶切割扩增的DNA。随后,根据其大小分离DNA片段。随后,将检测到的DNA片段的大小与对照进行比较。此方法的实例包括使用限制性片段长度多态性(RFLP)和PCR-RFLP的方法。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。随后,扩增在FLT3基因区域中含有突变位点的DNA。然后,将扩增的DNA解离成单链DNA。随后,在非变性凝胶上分离因此通过解离获得的单链DNA。将分离的单链DNA在凝胶上的迁移率与对照进行比较。此方法的实例包括PCR-SSCP(单链构象多态性)。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。随后,扩增在FLT3基因区域中含有突变位点的DNA。然后,在凝胶上分离扩增的DNA,在所述凝胶中逐渐升高DNA变性剂的浓度。随后,将分离的DNA在凝胶上的迁移率与对照进行比较。此方法的实例包括变性剂梯度凝胶电泳(DGGE)。
另一替代方法是使用从生物样品制备的在FLT3基因区域中含有突变位点的DNA和具有与DNA杂交的固定化寡核苷酸探针的基材的方法。此方法的实例包括DNA阵列方法。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。此外,制备“具有与FLT3基因区域中的突变位点处的碱基下游1个碱基处的碱基及其下游核苷酸序列互补的核苷酸序列的寡核苷酸引物”。随后,使用作为模板的DNA和引物进行ddNTP引物延伸反应。随后,将引物延伸反应产物应用于质谱仪以进行质谱分析。随后,从质谱分析结果确定基因型。然后,将确定的基因型与对照进行比较。此方法的实例包括MALDI-TOF/MS。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。随后,制备由5' - "与FLT3基因区域中的突变位点处的碱基及其上游核苷酸序列互补的核苷酸序列" - "既不与FLT3基因区域中的突变位点下游1个碱基处的碱基杂交,也不与其下游核苷酸序列杂交的核苷酸序列" - 3' (侧翼(flap))组成的寡核苷酸探针。此外,制备“具有与FLT3基因区域中的突变位点处的碱基及其下游核苷酸序列互补的核苷酸序列的寡核苷酸探针”。随后,将制备的DNA与这两种类型的寡核苷酸探针杂交。随后,用单链DNA切割酶切割杂交的DNA以释放侧翼。单链DNA切割酶的实例包括但不具体限于裂解酶。在该方法中,具有与侧翼互补的序列的荧光报道子和荧光猝灭剂标记的寡核苷酸探针然后与侧翼杂交。随后,测量生成的荧光的强度。然后,将测量的荧光强度与对照进行比较。此方法的实例包括侵入物方法。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。随后,扩增在FLT3基因区域中含有突变位点的DNA。然后,将扩增的DNA解离成单链,并且分离解离的DNA的单链中的仅一条。随后,从接近于FLT3基因区域中的突变位点处的碱基的碱基一个接一个进行延伸反应。酶促使得在该反应期间生成的焦磷酸发光。测量光的强度。将测量的荧光强度与对照进行比较。此方法的实例包括焦磷酸测序。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。随后,扩增在FLT3基因区域中含有突变位点的DNA。随后,制备“具有与FLT3基因区域中的突变位点处的碱基下游1个碱基处的碱基及其下游核苷酸序列互补的核苷酸序列的寡核苷酸引物”。随后,在荧光标记的核苷酸存在的情况下使用作为模板的扩增的DNA和制备的引物进行单碱基延伸反应。然后,测量荧光的偏振度。随后,将测量的荧光的偏振度与对照进行比较。此方法的实例包括AcycloPrime方法。
在另一替代方法中,首先从生物样品制备DNA或cDNA样品。随后,扩增在FLT3基因区域中含有突变位点的DNA。随后,制备“具有与FLT3基因区域中的突变位点处的碱基下游1个碱基处的碱基及其下游核苷酸序列互补的核苷酸序列的寡核苷酸引物”。随后,在荧光标记的核苷酸存在的情况下使用作为模板的扩增的DNA和制备的引物进行单碱基延伸反应。随后,确定用于单碱基延伸反应中的碱基种类。然后,将确定的碱基种类与对照进行比较。此方法的实例包括SNuPE方法。
如果突变导致FLT3蛋白中的氨基酸变化(例如,取代、缺失或插入),则从生物样品制备的样品可以是蛋白。在此情况下,使用特异性结合具有起因于突变的氨基酸变化的位点的分子(例如抗体)的方法可用于检测突变。
由于FLT3的活化突变提高了FLT3的磷酸化水平,FLT3的活化突变也可以通过磷酸化FLT3的定量来检测。本领域已知的磷酸化蛋白测量方法可用作用于定量测量磷酸化FLT3蛋白的方法。例如,可以利用使用针对磷酸化FLT3蛋白的抗体的各种方法。其具体实例可以包括Western印迹、免疫沉淀、酶联免疫吸附测定(ELISA)和放射免疫测定(RIA)。
可以适当地使用人源化抗体、小鼠抗体、大鼠抗体、兔抗体、绵羊抗体等作为针对突变的FLT3蛋白或磷酸化的FLT3蛋白的抗体,只要抗体针对作为抗原的突变的FLT3蛋白或磷酸化的FLT3蛋白且特异性结合抗原。抗体可以是多克隆抗体,或可以是单克隆抗体。从可以稳定地产生同质抗体的观点出发,优选单克隆抗体。多克隆抗体和单克隆抗体可以通过本领域技术人员众所周知的方法来制备。所需抗体也可以从市售的抗体中选择用于使用。
产生单克隆抗体的杂交瘤基本上可以通过使用如下的本领域已知的技术来制备:使用目标抗原或表达目标抗原的细胞作为致敏抗原,并且根据常规免疫方法用该致敏抗原免疫所需动物。通过常规细胞融合方法将获得的免疫细胞与已知的亲本细胞融合。然后,可以通过常规的筛选方法选择产生所需单克隆抗体的细胞(杂交瘤细胞)。杂交瘤的制备可以根据例如Millstein ("Methods of Enzymology", 1981, Vol. 73, p. 3-46)的方法进行。
在该上下文中,磷酸化的FLT3蛋白或其片段可用作用于制备单克隆抗体的抗原。本领域技术人员可以根据书籍(例如,Sambrook编, "Molecular Cloning:A LaboratoryManual", 第2版, Vol. 1-3, Cold Spring Harbor Laboratory Press, NY, 1989)中描述的方法容易地获得磷酸化的FLT3蛋白或其片段。
蛋白或其片段和抗体可以固定在支持物上并用于定量磷酸化的FLT3蛋白。支持物不受限制,只要支持物允许固定蛋白。其一般实例可以包括:无机材料,诸如玻璃板、硅片和树脂;天然聚合物材料,包括硝化纤维素;和合成聚合物材料,包括尼龙和聚苯乙烯。
用于检测FLT3的活化突变的方法的更具体的实例包括WO9817808及其相应的美国专利US6846630中描述的用于检测FLT3-ITD突变的方法(WO9817808和US6846630以其整体通过引用并入本文)。该方法可以通过使用商购自Takara Bio Inc.等的检测试剂盒进行。
使用从测试主体衍生的生物样品获得的mRNA进行RT-PCR、随后进行毛细管电泳的方法也可以用作另一种类似的方法(Leukemia, 2005, 19, 1479-1482,其以其整体通过引用并入本文)。
用于检测磷酸化的FLT3蛋白的方法的具体实例包括WO2010/054185(其以其整体通过引用并入本文)中描述的方法。
从另一观点来看,对MDM2抑制剂敏感的癌症和具有野生型TP53的癌症优选作为待治疗的癌症的类型。
上面提及作为用于证实FLT3中的突变的方法的各种方法可以类似地用作用于证实TP53为野生型的方法。其更具体的实例包括使用对于突变的DNA序列特异性的探针的微阵列方法(AmpliChip p53, Roche Molecular Systems, Inc.,等, http://www.ncbi.nlm.nih.gov/pubmed/21319261),使用对于突变的DNA序列特异性的探针的PCR(qBiomarker Somatic Mutation PCR Arrays, Qiagen N.V., 等),使用Sanger测序仪读取p53基因序列的方法(http://p53.iarc.fr/Download/TP53_DirectSequencing_IARC.pdf)和使用下一代测序仪读取p53基因序列的方法(TruSeq Amplicon - CancerPanel, Illumina http://www.illuminakk.co.jp/products/truseq_amplicon_cancer_panel.ilmn, Oncomine(R) Cancer Research Panel, Life Technologies Corp.,http://www.lifetechnologies.com/jp/ja/home/clinical/preclinical-companion-diagnostic-development/oncomine-cancer-research-panel-workflow.html,等)。
使用基因签名的方法也可以优选用作用于预测对MDM2抑制剂的敏感性的方法。用于预测对MDM2抑制剂的敏感性的基因签名的实例包括但不具体限于WO2014/020502中描述的基因群组(WO2014/020502以其整体通过引用并入本文)。更具体地,可以优选使用包含至少一种选自MDM2、CDKN1A、ZMAT3、DDB2、FDXR、RPS27L、BAX、RPM2B、SESN1、CCNG1、XPC、TNFSF10B和AEN的基因的基因群组(该基因群组可以包含所有这些基因)。其其他实例包括WO2015/000945中描述的基因群组(WO2014/000945以其整体通过引用并入本文)。更具体地,可以优选使用包含至少一种选自BAX、RPS27L、EDA2R、XPC、DDB2、FDXR、MDM2、CDKN1A、TRIAP1、BBC3、CCNG1、TNFRSF10B和CDKN2A的基因的基因群组(该基因群组可以包含所有这些基因)。基因群组中含有的基因数量不受限制。可以优选使用当基因签名中含有的基因高度表达时允许癌症被证实为对MDM2抑制剂敏感的敏感特征。
根据本发明的药物可以与额外抗肿瘤剂联合使用。其实例包括抗肿瘤抗生素、抗肿瘤植物成分、BRM(生物反应调节剂)、激素、维生素、抗肿瘤抗体、分子靶标药物、烷化剂、代谢拮抗剂和其他抗肿瘤剂。
更具体地,烷化剂的实例包括:烷化剂诸如氮芥、氮芥N-氧化物、苯达莫司汀和苯丁酸氮芥;氮丙啶烷化剂诸如卡波醌和噻替派;环氧化物烷化剂诸如二溴甘露醇和二溴卫矛醇;亚硝基脲烷化剂诸如卡莫司汀、洛莫司汀、司莫司汀、盐酸尼莫司汀、链脲霉素、氯脲霉素和雷莫司汀;以及白消安、甲苯磺酸英丙舒凡、替莫唑胺和达卡巴嗪。
代谢拮抗剂的各种实例包括:嘌呤代谢拮抗剂诸如6-巯基嘌呤、6-硫鸟嘌呤和硫肌苷;嘧啶代谢拮抗剂诸如氟尿嘧啶、替加氟、替加氟-尿嘧啶、卡莫氟、去氧氟尿苷、溴尿苷、阿糖胞苷和依诺他滨;和叶酸代谢拮抗剂诸如甲氨蝶呤和三甲曲沙。
抗肿瘤抗生素的实例包括:丝裂霉素C、博来霉素、培洛霉素、道诺霉素、阿柔比星、多柔比星、伊达比星、吡柔比星、THP-阿霉素、4'-表阿霉素和表柔比星;和色霉素A3和放线菌素D。
抗肿瘤植物成分及其衍生物的实例包括:长春花生物碱诸如长春地辛、长春新碱和长春花碱;紫杉烷类诸如紫杉醇、多西他赛和卡巴他赛;和表鬼臼毒素类诸如依托泊苷和替尼泊苷。
BRM的实例包括肿瘤坏死因子和吲哚美辛。
激素的实例包括氢化可的松、地塞米松、甲泼尼龙、泼尼松龙、普拉睾酮、倍他米松、去炎松、羟甲烯龙、诺龙、美替诺龙、磷雌酚、炔雌醇、氯地孕酮、米雄烷和甲羟孕酮。
维生素的实例包括维生素C和维生素A。
抗肿瘤抗体和分子靶标药物的实例包括曲妥珠单抗、利妥昔单抗、西妥昔单抗、尼妥珠单抗、地诺单抗、贝伐珠单抗、英夫利昔单抗、伊匹单抗、纳武单抗、派姆单抗、阿维单抗(avelumab)、pidilizumab、阿特朱单抗(atezolizumab)、雷莫芦单抗、甲磺酸伊马替尼、达沙替尼、吉非替尼、厄洛替尼、奥斯替尼(osimertinib)、舒尼替尼、拉帕替尼、达拉菲尼、曲美替尼、考比替尼、帕唑帕尼、帕博西尼、帕比司他、索拉非尼、克唑替尼、威罗菲尼、依鲁替尼、硼替佐米、卡菲佐米、艾沙佐米(ixazomib)和gilteritinib。
其他抗肿瘤剂的实例包括顺铂、卡铂、奥沙利铂、他莫昔芬、来曲唑、阿那曲唑、依西美坦、柠檬酸托瑞米芬、氟维司群、比卡鲁胺、氟他胺、米托坦、亮丙瑞林、醋酸戈舍瑞林、喜树碱、异环磷酰胺、环磷酰胺、美法仑、L-天冬酰胺酶、醋葡醛内酯、西索菲兰、毕西巴尼、丙卡巴肼、哌泊溴烷、新制癌菌素、羟基脲、乌苯美司、阿扎胞苷、地西他滨、沙利度胺、来那度胺、泊马度胺、艾瑞布林、维甲酸和krestin。
本发明的另一个方面涉及用于预测对用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐联合治疗癌症的反应性的方法,其包括使用测试主体衍生的生物样品,检测生物样品中含有的FLT3的活化突变的存在或不存在,和证实具有检测的FLT3的活化突变的测试主体对用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐联合治疗癌症有反应。
本发明的一个替代方面涉及用于选择主体用于用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐联合治疗癌症的方法,其包括使用测试主体衍生的生物样品,检测生物样品中的FLT3的活化突变的存在或不存在,和选择具有检测到的FLT3的活化突变的测试主体作为用于用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐联合治疗癌症的主体。
本发明还涉及用于预测对癌症治疗的反应性的方法或用于选择主体用于治疗癌症的方法,其中FLT3的活化突变是FLT3-ITD突变。
用于收集测试主体衍生的生物样品的方法和用于检测生物样品中的FLT3的活化突变或FLT3-ITD突变的方法如上所提及。
实施例
在下文中,将参照下面给出的实施例具体解释本发明。然而,本发明不限于这些实施例,并且它们不应以任何限制性方式解释。
(测试例1 对化合物A和奎扎替尼的联合使用的体内效果的研究)
使用磷酸盐缓冲盐水将具有FLT3-ITD突变和野生型TP53的人急性骨髓性白血病细胞系MOLM-13细胞悬浮至5 × 107个细胞/mL。将0.1mL制备的细胞悬浮液皮下移植至每只NOD-SCID小鼠(雄性,5至7周龄)。在肿瘤接种后6天,在证实平均肿瘤体积超过100 mm3后,将小鼠基于其肿瘤体积值随机化(N = 6/组)。将25 mg/kg或50 mg/kg化合物A或0.5 mg/kg或1 mg/kg奎扎替尼(LC Laboratories)通过口服管饲施用于小鼠。对于联合使用组,通过强制施用来依次口服施用25 mg/kg或50 mg/kg化合物A和0.5 mg/kg或1 mg/kg奎扎替尼。从随机化之日(肿瘤接种后6天)起,连续5天(肿瘤接种后6至10天)每天一次进行施用,并且在2天药物假期后,连续4天(肿瘤接种后13至16天)每天一次进行施用。使用电子数字卡尺随时间测量肿瘤的长度(mm)和宽度(mm)。在评估中使用根据下示的计算公式(4)计算的评价之日(肿瘤接种后17天)的肿瘤生长抑制%(TGI%)。此外,使用小动物的自动平衡随时间来测量体重,并且根据下示的计算公式(5)来计算体重变化%,以评价药物施用对体重的影响。此外,在剂量计算中使用最后体重测量的结果。
TGI (%) = (1 - A / B) × 100 ... (4)
A:在评价之日的化合物施用组的平均肿瘤体积(*)
B:在评价之日的未处理对照组的平均肿瘤体积(*)
*:根据1/2 × [肿瘤的长轴] × [肿瘤的短轴] × [肿瘤的短轴]计算肿瘤体积。
体重变化(%) = 个体的平均体重变化% ... (5)
每个个体的体重变化% = (1 - BWn / BWs) × 100
BWn: 第n天的体重
BWs:施用开始日的体重
结果显示于图1和表1至3中。
[表1]
[表2]
[表3]
序列表的自由文本
SEQ ID NO: 1: 编码FLT3蛋白(SEQ ID NO: 2)的FLT3 mRNA。
SEQ ID NO: 2: FLT3蛋白的氨基酸序列
SEQ ID NO: 3: 编码TP53蛋白(SEQ ID NO: 4)的TP53 mRNA。
SEQ ID NO: 4: TP53蛋白的氨基酸序列
序列表
<110> DAIICHI SANKYO COMPANY, LIMITED
<120> 用于治疗癌症的联合方法
<130> FP1601
<150> JP2015-032201
<151> 2015-02-20
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 3848
<212> DNA
<213> 智人
<220>
<221> 尚未归类的特征
<223> 编码FLT3蛋白(SEQ ID NO. 2)的FLT3 mRNA
<220>
<221> CDS
<222> (83)..(3064)
<400> 1
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gggaccccgg gctccggagg cc atg ccg gcg ttg gcg cgc gac ggc ggc cag 112
Met Pro Ala Leu Ala Arg Asp Gly Gly Gln
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Leu Pro Leu Leu Val Val Phe Ser Ala Met Ile Phe Gly Thr Ile Thr
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Asn Gln Asp Leu Pro Val Ile Lys Cys Val Leu Ile Asn His Lys Asn
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Asn Asp Ser Ser Val Gly Lys Ser Ser Ser Tyr Pro Met Val Ser Glu
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Ser Pro Glu Asp Leu Gly Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr
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Val Tyr Glu Ala Ala Ala Val Glu Val Asp Val Ser Ala Ser Ile Thr
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Leu Gln Val Leu Val Asp Ala Pro Gly Asn Ile Ser Cys Leu Trp Val
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Phe Lys His Ser Ser Leu Asn Cys Gln Pro His Phe Asp Leu Gln Asn
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Arg Gly Val Val Ser Met Val Ile Leu Lys Met Thr Glu Thr Gln Ala
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Gly Glu Tyr Leu Leu Phe Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile
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Leu Phe Thr Val Ser Ile Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg
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Pro Tyr Phe Arg Lys Met Glu Asn Gln Asp Ala Leu Val Cys Ile Ser
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Glu Ser Val Pro Glu Pro Ile Val Glu Trp Val Leu Cys Asp Ser Gln
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ggg gaa agc tgt aaa gaa gaa agt cca gct gtt gtt aaa aag gag gaa 736
Gly Glu Ser Cys Lys Glu Glu Ser Pro Ala Val Val Lys Lys Glu Glu
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Lys Val Leu His Glu Leu Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg
220 225 230
aat gaa ctg ggc agg gaa tgc acc agg ctg ttc aca ata gat cta aat 832
Asn Glu Leu Gly Arg Glu Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn
235 240 245 250
caa act cct cag acc aca ttg cca caa tta ttt ctt aaa gta ggg gaa 880
Gln Thr Pro Gln Thr Thr Leu Pro Gln Leu Phe Leu Lys Val Gly Glu
255 260 265
ccc tta tgg ata agg tgc aaa gct gtt cat gtg aac cat gga ttc ggg 928
Pro Leu Trp Ile Arg Cys Lys Ala Val His Val Asn His Gly Phe Gly
270 275 280
ctc acc tgg gaa tta gaa aac aaa gca ctc gag gag ggc aac tac ttt 976
Leu Thr Trp Glu Leu Glu Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe
285 290 295
gag atg agt acc tat tca aca aac aga act atg ata cgg att ctg ttt 1024
Glu Met Ser Thr Tyr Ser Thr Asn Arg Thr Met Ile Arg Ile Leu Phe
300 305 310
gct ttt gta tca tca gtg gca aga aac gac acc gga tac tac act tgt 1072
Ala Phe Val Ser Ser Val Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys
315 320 325 330
tcc tct tca aag cat ccc agt caa tca gct ttg gtt acc atc gta gaa 1120
Ser Ser Ser Lys His Pro Ser Gln Ser Ala Leu Val Thr Ile Val Glu
335 340 345
aag gga ttt ata aat gct acc aat tca agt gaa gat tat gaa att gac 1168
Lys Gly Phe Ile Asn Ala Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp
350 355 360
caa tat gaa gag ttt tgt ttt tct gtc agg ttt aaa gcc tac cca caa 1216
Gln Tyr Glu Glu Phe Cys Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln
365 370 375
atc aga tgt acg tgg acc ttc tct cga aaa tca ttt cct tgt gag caa 1264
Ile Arg Cys Thr Trp Thr Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln
380 385 390
aag ggt ctt gat aac gga tac agc ata tcc aag ttt tgc aat cat aag 1312
Lys Gly Leu Asp Asn Gly Tyr Ser Ile Ser Lys Phe Cys Asn His Lys
395 400 405 410
cac cag cca gga gaa tat ata ttc cat gca gaa aat gat gat gcc caa 1360
His Gln Pro Gly Glu Tyr Ile Phe His Ala Glu Asn Asp Asp Ala Gln
415 420 425
ttt acc aaa atg ttc acg ctg aat ata aga agg aaa cct caa gtg ctc 1408
Phe Thr Lys Met Phe Thr Leu Asn Ile Arg Arg Lys Pro Gln Val Leu
430 435 440
gca gaa gca tcg gca agt cag gcg tcc tgt ttc tcg gat gga tac cca 1456
Ala Glu Ala Ser Ala Ser Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro
445 450 455
tta cca tct tgg acc tgg aag aag tgt tca gac aag tct ccc aac tgc 1504
Leu Pro Ser Trp Thr Trp Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys
460 465 470
aca gaa gag atc aca gaa gga gtc tgg aat aga aag gct aac aga aaa 1552
Thr Glu Glu Ile Thr Glu Gly Val Trp Asn Arg Lys Ala Asn Arg Lys
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gtg ttt gga cag tgg gtg tcg agc agt act cta aac atg agt gaa gcc 1600
Val Phe Gly Gln Trp Val Ser Ser Ser Thr Leu Asn Met Ser Glu Ala
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ata aaa ggg ttc ctg gtc aag tgc tgt gca tac aat tcc ctt ggc aca 1648
Ile Lys Gly Phe Leu Val Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr
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tct tgt gag acg atc ctt tta aac tct cca ggc ccc ttc cct ttc atc 1696
Ser Cys Glu Thr Ile Leu Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile
525 530 535
caa gac aac atc tca ttc tat gca aca att ggt gtt tgt ctc ctc ttc 1744
Gln Asp Asn Ile Ser Phe Tyr Ala Thr Ile Gly Val Cys Leu Leu Phe
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att gtc gtt tta acc ctg cta att tgt cac aag tac aaa aag caa ttt 1792
Ile Val Val Leu Thr Leu Leu Ile Cys His Lys Tyr Lys Lys Gln Phe
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agg tat gaa agc cag cta cag atg gta cag gtg acc ggc tcc tca gat 1840
Arg Tyr Glu Ser Gln Leu Gln Met Val Gln Val Thr Gly Ser Ser Asp
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aat gag tac ttc tac gtt gat ttc aga gaa tat gaa tat gat ctc aaa 1888
Asn Glu Tyr Phe Tyr Val Asp Phe Arg Glu Tyr Glu Tyr Asp Leu Lys
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Trp Glu Phe Pro Arg Glu Asn Leu Glu Phe Gly Lys Val Leu Gly Ser
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Gly Ala Phe Gly Lys Val Met Asn Ala Thr Ala Tyr Gly Ile Ser Lys
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Thr Gly Val Ser Ile Gln Val Ala Val Lys Met Leu Lys Glu Lys Ala
635 640 645 650
gac agc tct gaa aga gag gca ctc atg tca gaa ctc aag atg atg acc 2080
Asp Ser Ser Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Met Met Thr
655 660 665
cag ctg gga agc cac gag aat att gtg aac ctg ctg ggg gcg tgc aca 2128
Gln Leu Gly Ser His Glu Asn Ile Val Asn Leu Leu Gly Ala Cys Thr
670 675 680
ctg tca gga cca att tac ttg att ttt gaa tac tgt tgc tat ggt gat 2176
Leu Ser Gly Pro Ile Tyr Leu Ile Phe Glu Tyr Cys Cys Tyr Gly Asp
685 690 695
ctt ctc aac tat cta aga agt aaa aga gaa aaa ttt cac agg act tgg 2224
Leu Leu Asn Tyr Leu Arg Ser Lys Arg Glu Lys Phe His Arg Thr Trp
700 705 710
aca gag att ttc aag gaa cac aat ttc agt ttt tac ccc act ttc caa 2272
Thr Glu Ile Phe Lys Glu His Asn Phe Ser Phe Tyr Pro Thr Phe Gln
715 720 725 730
tca cat cca aat tcc agc atg cct ggt tca aga gaa gtt cag ata cac 2320
Ser His Pro Asn Ser Ser Met Pro Gly Ser Arg Glu Val Gln Ile His
735 740 745
ccg gac tcg gat caa atc tca ggg ctt cat ggg aat tca ttt cac tct 2368
Pro Asp Ser Asp Gln Ile Ser Gly Leu His Gly Asn Ser Phe His Ser
750 755 760
gaa gat gaa att gaa tat gaa aac caa aaa agg ctg gaa gaa gag gag 2416
Glu Asp Glu Ile Glu Tyr Glu Asn Gln Lys Arg Leu Glu Glu Glu Glu
765 770 775
gac ttg aat gtg ctt aca ttt gaa gat ctt ctt tgc ttt gca tat caa 2464
Asp Leu Asn Val Leu Thr Phe Glu Asp Leu Leu Cys Phe Ala Tyr Gln
780 785 790
gtt gcc aaa gga atg gaa ttt ctg gaa ttt aag tcg tgt gtt cac aga 2512
Val Ala Lys Gly Met Glu Phe Leu Glu Phe Lys Ser Cys Val His Arg
795 800 805 810
gac ctg gcc gcc agg aac gtg ctt gtc acc cac ggg aaa gtg gtg aag 2560
Asp Leu Ala Ala Arg Asn Val Leu Val Thr His Gly Lys Val Val Lys
815 820 825
ata tgt gac ttt gga ttg gct cga gat atc atg agt gat tcc aac tat 2608
Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile Met Ser Asp Ser Asn Tyr
830 835 840
gtt gtc agg ggc aat gcc cgt ctg cct gta aaa tgg atg gcc ccc gaa 2656
Val Val Arg Gly Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu
845 850 855
agc ctg ttt gaa ggc atc tac acc att aag agt gat gtc tgg tca tat 2704
Ser Leu Phe Glu Gly Ile Tyr Thr Ile Lys Ser Asp Val Trp Ser Tyr
860 865 870
gga ata tta ctg tgg gaa atc ttc tca ctt ggt gtg aat cct tac cct 2752
Gly Ile Leu Leu Trp Glu Ile Phe Ser Leu Gly Val Asn Pro Tyr Pro
875 880 885 890
ggc att ccg gtt gat gct aac ttc tac aaa ctg att caa aat gga ttt 2800
Gly Ile Pro Val Asp Ala Asn Phe Tyr Lys Leu Ile Gln Asn Gly Phe
895 900 905
aaa atg gat cag cca ttt tat gct aca gaa gaa ata tac att ata atg 2848
Lys Met Asp Gln Pro Phe Tyr Ala Thr Glu Glu Ile Tyr Ile Ile Met
910 915 920
caa tcc tgc tgg gct ttt gac tca agg aaa cgg cca tcc ttc cct aat 2896
Gln Ser Cys Trp Ala Phe Asp Ser Arg Lys Arg Pro Ser Phe Pro Asn
925 930 935
ttg act tcg ttt tta gga tgt cag ctg gca gat gca gaa gaa gcg atg 2944
Leu Thr Ser Phe Leu Gly Cys Gln Leu Ala Asp Ala Glu Glu Ala Met
940 945 950
tat cag aat gtg gat ggc cgt gtt tcg gaa tgt cct cac acc tac caa 2992
Tyr Gln Asn Val Asp Gly Arg Val Ser Glu Cys Pro His Thr Tyr Gln
955 960 965 970
aac agg cga cct ttc agc aga gag atg gat ttg ggg cta ctc tct ccg 3040
Asn Arg Arg Pro Phe Ser Arg Glu Met Asp Leu Gly Leu Leu Ser Pro
975 980 985
cag gct cag gtc gaa gat tcg tag aggaacaatt tagttttaag gacttcatcc 3094
Gln Ala Gln Val Glu Asp Ser
990
ctccacctat ccctaacagg ctgtagatta ccaaaacaag attaatttca tcactaaaag 3154
aaaatctatt atcaactgct gcttcaccag acttttctct agaagctgtc tgcgtttact 3214
cttgttttca aagggacttt tgtaaaatca aatcatcctg tcacaaggca ggaggagctg 3274
ataatgaact ttattggagc attgatctgc atccaaggcc ttctcaggct ggcttgagtg 3334
aattgtgtac ctgaagtaca gtatattctt gtaaatacat aaaacaaaag cattttgcta 3394
aggagaagct aatatgattt tttaagtcta tgttttaaaa taatatgtaa atttttcagc 3454
tatttagtga tatattttat gggtgggaat aaaatttcta ctacagaatt gcccattatt 3514
gaattattta catggtataa ttagggcaag tcttaactgg agttcacgaa ccccctgaaa 3574
ttgtgcaccc atagccacct acacattcct tccagagcac gtgtgctttt accccaagat 3634
acaaggaatg tgtaggcagc tatggttgtc acagcctaag atttctgcaa caacaggggt 3694
tgtattgggg gaagtttata atgaataggt gttctaccat aaagagtaat acatcaccta 3754
gacactttgg cggccttccc agactcaggg ccagtcagaa gtaacatgga ggattagtat 3814
tttcaataaa gttactcttg tccccacaaa aaaa 3848
<210> 2
<211> 993
<212> PRT
<213> 智人
<400> 2
Met Pro Ala Leu Ala Arg Asp Gly Gly Gln Leu Pro Leu Leu Val Val
1 5 10 15
Phe Ser Ala Met Ile Phe Gly Thr Ile Thr Asn Gln Asp Leu Pro Val
20 25 30
Ile Lys Cys Val Leu Ile Asn His Lys Asn Asn Asp Ser Ser Val Gly
35 40 45
Lys Ser Ser Ser Tyr Pro Met Val Ser Glu Ser Pro Glu Asp Leu Gly
50 55 60
Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr Val Tyr Glu Ala Ala Ala
65 70 75 80
Val Glu Val Asp Val Ser Ala Ser Ile Thr Leu Gln Val Leu Val Asp
85 90 95
Ala Pro Gly Asn Ile Ser Cys Leu Trp Val Phe Lys His Ser Ser Leu
100 105 110
Asn Cys Gln Pro His Phe Asp Leu Gln Asn Arg Gly Val Val Ser Met
115 120 125
Val Ile Leu Lys Met Thr Glu Thr Gln Ala Gly Glu Tyr Leu Leu Phe
130 135 140
Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile Leu Phe Thr Val Ser Ile
145 150 155 160
Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg Pro Tyr Phe Arg Lys Met
165 170 175
Glu Asn Gln Asp Ala Leu Val Cys Ile Ser Glu Ser Val Pro Glu Pro
180 185 190
Ile Val Glu Trp Val Leu Cys Asp Ser Gln Gly Glu Ser Cys Lys Glu
195 200 205
Glu Ser Pro Ala Val Val Lys Lys Glu Glu Lys Val Leu His Glu Leu
210 215 220
Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg Asn Glu Leu Gly Arg Glu
225 230 235 240
Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn Gln Thr Pro Gln Thr Thr
245 250 255
Leu Pro Gln Leu Phe Leu Lys Val Gly Glu Pro Leu Trp Ile Arg Cys
260 265 270
Lys Ala Val His Val Asn His Gly Phe Gly Leu Thr Trp Glu Leu Glu
275 280 285
Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe Glu Met Ser Thr Tyr Ser
290 295 300
Thr Asn Arg Thr Met Ile Arg Ile Leu Phe Ala Phe Val Ser Ser Val
305 310 315 320
Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys Ser Ser Ser Lys His Pro
325 330 335
Ser Gln Ser Ala Leu Val Thr Ile Val Glu Lys Gly Phe Ile Asn Ala
340 345 350
Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp Gln Tyr Glu Glu Phe Cys
355 360 365
Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln Ile Arg Cys Thr Trp Thr
370 375 380
Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln Lys Gly Leu Asp Asn Gly
385 390 395 400
Tyr Ser Ile Ser Lys Phe Cys Asn His Lys His Gln Pro Gly Glu Tyr
405 410 415
Ile Phe His Ala Glu Asn Asp Asp Ala Gln Phe Thr Lys Met Phe Thr
420 425 430
Leu Asn Ile Arg Arg Lys Pro Gln Val Leu Ala Glu Ala Ser Ala Ser
435 440 445
Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro Leu Pro Ser Trp Thr Trp
450 455 460
Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys Thr Glu Glu Ile Thr Glu
465 470 475 480
Gly Val Trp Asn Arg Lys Ala Asn Arg Lys Val Phe Gly Gln Trp Val
485 490 495
Ser Ser Ser Thr Leu Asn Met Ser Glu Ala Ile Lys Gly Phe Leu Val
500 505 510
Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr Ser Cys Glu Thr Ile Leu
515 520 525
Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile Gln Asp Asn Ile Ser Phe
530 535 540
Tyr Ala Thr Ile Gly Val Cys Leu Leu Phe Ile Val Val Leu Thr Leu
545 550 555 560
Leu Ile Cys His Lys Tyr Lys Lys Gln Phe Arg Tyr Glu Ser Gln Leu
565 570 575
Gln Met Val Gln Val Thr Gly Ser Ser Asp Asn Glu Tyr Phe Tyr Val
580 585 590
Asp Phe Arg Glu Tyr Glu Tyr Asp Leu Lys Trp Glu Phe Pro Arg Glu
595 600 605
Asn Leu Glu Phe Gly Lys Val Leu Gly Ser Gly Ala Phe Gly Lys Val
610 615 620
Met Asn Ala Thr Ala Tyr Gly Ile Ser Lys Thr Gly Val Ser Ile Gln
625 630 635 640
Val Ala Val Lys Met Leu Lys Glu Lys Ala Asp Ser Ser Glu Arg Glu
645 650 655
Ala Leu Met Ser Glu Leu Lys Met Met Thr Gln Leu Gly Ser His Glu
660 665 670
Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Leu Ser Gly Pro Ile Tyr
675 680 685
Leu Ile Phe Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Tyr Leu Arg
690 695 700
Ser Lys Arg Glu Lys Phe His Arg Thr Trp Thr Glu Ile Phe Lys Glu
705 710 715 720
His Asn Phe Ser Phe Tyr Pro Thr Phe Gln Ser His Pro Asn Ser Ser
725 730 735
Met Pro Gly Ser Arg Glu Val Gln Ile His Pro Asp Ser Asp Gln Ile
740 745 750
Ser Gly Leu His Gly Asn Ser Phe His Ser Glu Asp Glu Ile Glu Tyr
755 760 765
Glu Asn Gln Lys Arg Leu Glu Glu Glu Glu Asp Leu Asn Val Leu Thr
770 775 780
Phe Glu Asp Leu Leu Cys Phe Ala Tyr Gln Val Ala Lys Gly Met Glu
785 790 795 800
Phe Leu Glu Phe Lys Ser Cys Val His Arg Asp Leu Ala Ala Arg Asn
805 810 815
Val Leu Val Thr His Gly Lys Val Val Lys Ile Cys Asp Phe Gly Leu
820 825 830
Ala Arg Asp Ile Met Ser Asp Ser Asn Tyr Val Val Arg Gly Asn Ala
835 840 845
Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Leu Phe Glu Gly Ile
850 855 860
Tyr Thr Ile Lys Ser Asp Val Trp Ser Tyr Gly Ile Leu Leu Trp Glu
865 870 875 880
Ile Phe Ser Leu Gly Val Asn Pro Tyr Pro Gly Ile Pro Val Asp Ala
885 890 895
Asn Phe Tyr Lys Leu Ile Gln Asn Gly Phe Lys Met Asp Gln Pro Phe
900 905 910
Tyr Ala Thr Glu Glu Ile Tyr Ile Ile Met Gln Ser Cys Trp Ala Phe
915 920 925
Asp Ser Arg Lys Arg Pro Ser Phe Pro Asn Leu Thr Ser Phe Leu Gly
930 935 940
Cys Gln Leu Ala Asp Ala Glu Glu Ala Met Tyr Gln Asn Val Asp Gly
945 950 955 960
Arg Val Ser Glu Cys Pro His Thr Tyr Gln Asn Arg Arg Pro Phe Ser
965 970 975
Arg Glu Met Asp Leu Gly Leu Leu Ser Pro Gln Ala Gln Val Glu Asp
980 985 990
Ser
<210> 3
<211> 2591
<212> DNA
<213> 智人
<220>
<221> 尚未归类的特征
<223> 编码TP53蛋白(SEQ ID NO. 4)的TP53 mRNA
<220>
<221> CDS
<222> (203)..(1384)
<400> 3
gatgggattg gggttttccc ctcccatgtg ctcaagactg gcgctaaaag ttttgagctt 60
ctcaaaagtc tagagccacc gtccagggag caggtagctg ctgggctccg gggacacttt 120
gcgttcgggc tgggagcgtg ctttccacga cggtgacacg cttccctgga ttggcagcca 180
gactgccttc cgggtcactg cc atg gag gag ccg cag tca gat cct agc gtc 232
Met Glu Glu Pro Gln Ser Asp Pro Ser Val
1 5 10
gag ccc cct ctg agt cag gaa aca ttt tca gac cta tgg aaa cta ctt 280
Glu Pro Pro Leu Ser Gln Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu
15 20 25
cct gaa aac aac gtt ctg tcc ccc ttg ccg tcc caa gca atg gat gat 328
Pro Glu Asn Asn Val Leu Ser Pro Leu Pro Ser Gln Ala Met Asp Asp
30 35 40
ttg atg ctg tcc ccg gac gat att gaa caa tgg ttc act gaa gac cca 376
Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro
45 50 55
ggt cca gat gaa gct ccc aga atg cca gag gct gct ccc ccc gtg gcc 424
Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro Pro Val Ala
60 65 70
cct gca cca gca gct cct aca ccg gcg gcc cct gca cca gcc ccc tcc 472
Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser
75 80 85 90
tgg ccc ctg tca tct tct gtc cct tcc cag aaa acc tac cag ggc agc 520
Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser
95 100 105
tac ggt ttc cgt ctg ggc ttc ttg cat tct ggg aca gcc aag tct gtg 568
Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val
110 115 120
act tgc acg tac tcc cct gcc ctc aac aag atg ttt tgc caa ctg gcc 616
Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys Gln Leu Ala
125 130 135
aag acc tgc cct gtg cag ctg tgg gtt gat tcc aca ccc ccg ccc ggc 664
Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro Pro Pro Gly
140 145 150
acc cgc gtc cgc gcc atg gcc atc tac aag cag tca cag cac atg acg 712
Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln His Met Thr
155 160 165 170
gag gtt gtg agg cgc tgc ccc cac cat gag cgc tgc tca gat agc gat 760
Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser Asp Ser Asp
175 180 185
ggt ctg gcc cct cct cag cat ctt atc cga gtg gaa gga aat ttg cgt 808
Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly Asn Leu Arg
190 195 200
gtg gag tat ttg gat gac aga aac act ttt cga cat agt gtg gtg gtg 856
Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser Val Val Val
205 210 215
ccc tat gag ccg cct gag gtt ggc tct gac tgt acc acc atc cac tac 904
Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr Ile His Tyr
220 225 230
aac tac atg tgt aac agt tcc tgc atg ggc ggc atg aac cgg agg ccc 952
Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn Arg Arg Pro
235 240 245 250
atc ctc acc atc atc aca ctg gaa gac tcc agt ggt aat cta ctg gga 1000
Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly
255 260 265
cgg aac agc ttt gag gtg cgt gtt tgt gcc tgt cct ggg aga gac cgg 1048
Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly Arg Asp Arg
270 275 280
cgc aca gag gaa gag aat ctc cgc aag aaa ggg gag cct cac cac gag 1096
Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro His His Glu
285 290 295
ctg ccc cca ggg agc act aag cga gca ctg ccc aac aac acc agc tcc 1144
Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser
300 305 310
tct ccc cag cca aag aag aaa cca ctg gat gga gaa tat ttc acc ctt 1192
Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu
315 320 325 330
cag atc cgt ggg cgt gag cgc ttc gag atg ttc cga gag ctg aat gag 1240
Gln Ile Arg Gly Arg Glu Arg Phe Glu Met Phe Arg Glu Leu Asn Glu
335 340 345
gcc ttg gaa ctc aag gat gcc cag gct ggg aag gag cca ggg ggg agc 1288
Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser
350 355 360
agg gct cac tcc agc cac ctg aag tcc aaa aag ggt cag tct acc tcc 1336
Arg Ala His Ser Ser His Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser
365 370 375
cgc cat aaa aaa ctc atg ttc aag aca gaa ggg cct gac tca gac tga 1384
Arg His Lys Lys Leu Met Phe Lys Thr Glu Gly Pro Asp Ser Asp
380 385 390
cattctccac ttcttgttcc ccactgacag cctcccaccc ccatctctcc ctcccctgcc 1444
attttgggtt ttgggtcttt gaacccttgc ttgcaatagg tgtgcgtcag aagcacccag 1504
gacttccatt tgctttgtcc cggggctcca ctgaacaagt tggcctgcac tggtgttttg 1564
ttgtggggag gaggatgggg agtaggacat accagcttag attttaaggt ttttactgtg 1624
agggatgttt gggagatgta agaaatgttc ttgcagttaa gggttagttt acaatcagcc 1684
acattctagg taggggccca cttcaccgta ctaaccaggg aagctgtccc tcactgttga 1744
attttctcta acttcaaggc ccatatctgt gaaatgctgg catttgcacc tacctcacag 1804
agtgcattgt gagggttaat gaaataatgt acatctggcc ttgaaaccac cttttattac 1864
atggggtcta gaacttgacc cccttgaggg tgcttgttcc ctctccctgt tggtcggtgg 1924
gttggtagtt tctacagttg ggcagctggt taggtagagg gagttgtcaa gtctctgctg 1984
gcccagccaa accctgtctg acaacctctt ggtgaacctt agtacctaaa aggaaatctc 2044
accccatccc acaccctgga ggatttcatc tcttgtatat gatgatctgg atccaccaag 2104
acttgtttta tgctcagggt caatttcttt tttctttttt tttttttttt ttctttttct 2164
ttgagactgg gtctcgcttt gttgcccagg ctggagtgga gtggcgtgat cttggcttac 2224
tgcagccttt gcctccccgg ctcgagcagt cctgcctcag cctccggagt agctgggacc 2284
acaggttcat gccaccatgg ccagccaact tttgcatgtt ttgtagagat ggggtctcac 2344
agtgttgccc aggctggtct caaactcctg ggctcaggcg atccacctgt ctcagcctcc 2404
cagagtgctg ggattacaat tgtgagccac cacgtccagc tggaagggtc aacatctttt 2464
acattctgca agcacatctg cattttcacc ccacccttcc cctccttctc cctttttata 2524
tcccattttt atatcgatct cttattttac aataaaactt tgctgccacc tgtgtgtctg 2584
aggggtg 2591
<210> 4
<211> 393
<212> PRT
<213> 智人
<400> 4
Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu
20 25 30
Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp
35 40 45
Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro
50 55 60
Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro
65 70 75 80
Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser
85 90 95
Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly
100 105 110
Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro
115 120 125
Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln
130 135 140
Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met
145 150 155 160
Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys
165 170 175
Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln
180 185 190
His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp
195 200 205
Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu
210 215 220
Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser
225 230 235 240
Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr
245 250 255
Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val
260 265 270
Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn
275 280 285
Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr
290 295 300
Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys
305 310 315 320
Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu
325 330 335
Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp
340 345 350
Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His
355 360 365
Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met
370 375 380
Phe Lys Thr Glu Gly Pro Asp Ser Asp
385 390
Claims (25)
1.用于癌症治疗的药物,其包含联合施用的(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐。
2.根据权利要求1所述的药物,其中(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐分别作为活性成分包含在不同的制剂中并且同时或不同时间施用。
3.根据权利要求1所述的药物,其中(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐包含在单一制剂中。
4.根据权利要求1所述的药物,其中所述药物是包含(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐的药剂盒制剂。
5.用于治疗癌症的方法,其包括联合施用(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐。
6.根据权利要求1至4中任一项所述的药物,其中所述化合物的各自盐是(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺对甲苯磺酸盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲二盐酸盐。
7.根据权利要求5所述的治疗方法,其中所述化合物的各自盐是(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰基四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺对甲苯磺酸盐和N-(5-叔丁基-异噁唑-3-基)-N'-{4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲二盐酸盐。
8.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是血癌(白血病、淋巴瘤或多发性骨髓瘤)、脑肿瘤、头颈癌、食管癌、胃癌、阑尾癌、结肠癌、肛门癌、胆囊癌、胆管癌、胰腺癌、胃肠道间质瘤、肺癌、肝癌、间皮瘤、甲状腺癌、肾癌、前列腺癌、神经内分泌肿瘤、黑色素瘤、乳腺癌、子宫内膜癌、子宫颈癌、卵巢癌、骨肉瘤、软组织肉瘤、卡波西肉瘤、肌肉瘤、肾癌、膀胱癌或睾丸癌。
9.根据权利要求5或7所述的治疗方法,其中所述癌症是血癌(白血病、淋巴瘤或多发性骨髓瘤)、脑肿瘤、头颈癌、食管癌、胃癌、阑尾癌、结肠癌、肛门癌、胆囊癌、胆管癌、胰腺癌、胃肠道间质瘤、肺癌、肝癌、间皮瘤、甲状腺癌、肾癌、前列腺癌、神经内分泌肿瘤、黑色素瘤、乳腺癌、子宫内膜癌、子宫颈癌、卵巢癌、骨肉瘤、软组织肉瘤、卡波西肉瘤、肌肉瘤、肾癌、膀胱癌或睾丸癌。
10.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是白血病。
11.根据权利要求5或7所述的治疗方法,其中所述癌症是白血病。
12.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是具有FLT3的活化突变的白血病。
13.根据权利要求5或7所述的治疗方法,其中所述癌症是具有FLT3的活化突变的白血病。
14.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是急性骨髓性白血病(AML)。
15.根据权利要求5或7所述的治疗方法,其中所述癌症是急性骨髓性白血病(AML)。
16.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是具有FLT3-ITD突变的急性骨髓性白血病(AML)。
17.根据权利要求5或7所述的治疗方法,其中所述癌症是具有FLT3-ITD突变的急性骨髓性白血病(AML)。
18.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是具有野生型TP53的癌症。
19.根据权利要求5或7所述的治疗方法,其中所述癌症是具有野生型TP53的癌症。
20.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是使用基因签名证实为MDM2抑制剂敏感的癌症。
21.根据权利要求5或7所述的治疗方法,其中所述癌症是使用基因签名确定为MDM2抑制剂敏感的癌症。
22.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是具有FLT3的活化突变且具有野生型TP53的癌症。
23.根据权利要求5或7所述的治疗方法,其中所述癌症是具有FLT3的活化突变且具有野生型TP53的癌症。
24.根据权利要求1至4和6中任一项所述的药物,其中所述癌症是具有FLT3的活化突变且使用基因签名确定为MDM2抑制剂敏感的癌症。
25.根据权利要求5或7所述的治疗方法,其中所述癌症是具有FLT3的活化突变且使用基因签名确定为MDM2抑制剂敏感的癌症。
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