CN115869325A - 化合物用于制备治疗kras突变癌症患者的药物的用途 - Google Patents
化合物用于制备治疗kras突变癌症患者的药物的用途 Download PDFInfo
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- CN115869325A CN115869325A CN202111130589.3A CN202111130589A CN115869325A CN 115869325 A CN115869325 A CN 115869325A CN 202111130589 A CN202111130589 A CN 202111130589A CN 115869325 A CN115869325 A CN 115869325A
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Abstract
本发明提供治疗KRAS突变的癌症、肿瘤患者的方法及制药用途。
Description
技术领域
本发明涉及癌症的治疗方法,特别是KRAS突变的癌症患者的治疗方法。
背景技术
KRAS基因的全名叫Kirsten ratsarcoma viral oncogene homolog,翻成中文是“Kirsten 大鼠肉瘤病毒癌基因同源物”。KRAS基因编码的蛋白是一种小GTP酶(smallGTPase),它属于RAS超蛋白家族,RAS基因包括KRAS,NRAS和HRAS三种,这些基因编码的蛋白是GTPases,在调控细胞增殖和存活的通路中起到分子开关的作用。基于目前的COSMI C数据显示,KRAS是三者中最常见的突变基因(22%),其次是NRAS(8%),最后是HRAS(3%)。KRAS基因对人类癌症影响很大,大约有30%的癌症患者都存在KRAS突变,其中包括90%的胰腺癌,50%的结肠癌和25%的肺癌。在非小细胞肺癌中,KRAS基因突变占2 0~30%,多存在于肺腺癌中,肺鳞癌中比较罕见。KRAS基因突变,主要集中在第12,13 及61号密码子位置,其中,第12号密码子位置的突变占到80%以上,包括G12A,G12C, G12D,G12R,G12S及G12V。KRAS基因被激活最常见的方式是点突变,95%的KRAS 突变主要发生在2号外显子的第12号密码子(>80%)和13号密码子上。在常见的突变形式有KRAS-G12C突变(占所有KRAS突变的13%),KRAS-G12V(20%)和KRAS-G1 2D(29%)突变(Loong HHF,Du N,ChengC,Lin H,Guo J,Lin G,Li M,Jiang T,S hi Z,Cui Y,Jin X,Yao J,Xing Y,Yao M,WangK,Mok TSK,Liu L.KRAS G12C mutations in Asia:A landscape analysis of 11,951Chinese tumor samples.Transl Lung Ca ncer Res 2020.doi:10.21037/tlcr-20-455)。
KRAS基因G12C突变,其突变体具有一个半胱氨酸残基(第12位的甘氨酸变成半胱氨酸),已被用于设计具有前期临床活性的共价抑制剂。比如AMG-510(临床开发的第一个KRAS-G12C抑制剂)和MRTX849,已表现出强抗肿瘤活性。
2021年5月29日,针对KRAS突变有效,被业界称为“革命性抗癌药”Sotorasib(AMG-510,Lumakras)获得FDA批准,用于治疗患有KRAS-G12C突变的非小细胞肺癌患者,这些患者至少接受过一种前期全身性治疗。AMG510是专门针对KRAS-G12C这种突变亚型的,具有很高的选择性,能与6,000多种蛋白质中的KRAS-G12C特异性结合,锁定并令其失活。
2021年6月24日,美国食品药品监督管理局(FDA)授予Adagrasib(阿达格拉西布,MRTX849)突破性疗法认定,用于治疗先前接受过全身治疗的携带KRAS-G12C突变的非小细胞肺癌(NSCLC)患者。该药是一款针对KRAS-G12C突变体的特异性优化口服抑制剂。通过在非活性状态下与KRAS-G12C不可逆转地选择性结合,阻止其发送细胞生长信号并导致癌细胞死亡,经过初步的人体临床试验证实,MRTX849在治疗携带KRAS-G12C基因突变的非小细胞肺癌(NSCLC)和结直肠癌(CRC)及其他实体肿瘤时表现出可喜的安全性和抗癌活性。
然而针对KRAS突变中的G12D这个更广泛的突变亚型却没有药物上市。
发明内容
AST-3424(OBI-3424)是一款first-in-class的以过表达醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化癌症治疗药物,它可以选择性靶向过度表达AKR1C3的癌症,并在AKR 1C3酶存在的情况下,选择性释放强效的DNA烷化剂。这种选择性激活模式将AST-3424 与传统的烷化剂(如环磷酰胺cyclophosphamide与异环磷酰胺ifosfamide)区分开来。AKR 1C3过度表达在多种治疗抵抗性和难治性癌症中存在,包括HCC、去势抵抗性前列腺癌(C RPC)和T细胞急性淋巴性白血病(T-ALL)。AKR1C3在多达15种实体瘤和血液肿瘤中均有高度表达。目前,该药物在中国和美国进行II期临床试验(美国OBI-3424-NCT03592 264-II期,去势前列腺癌和肝癌;美国OBI-3424-NCT04315324-II期,T淋巴细胞急性白血病T-ALL;中国AST-3424-CTR20191399-II期,实体瘤;中国AST-3424-CTR20201915 -II期,T淋巴细胞急性白血病T-ALL和B淋巴细胞急性白血病B-ALL)。
基于实验结果,本申请提供以下的治疗癌症方法和化合物的制药用途。
治疗方法,其使用含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者。
AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途。
AKR1C3活化的DNA烷化剂前药化合物是指该化合物为前药,该前药分子与AKR1C3酶反应,反应后释放出具有细胞毒性的DNA烷化剂。
具体的以AST-3424为例,这些化合物作为醛酮还原酶AKR1C3特异性底物,可仅在AK R1C3高表达的癌细胞内快速有效地还原,从而释放细胞毒素-DNA烷化剂AST-2660,AST-2660与DNA交联而使得癌细胞:
治疗方法,其使用含有含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者,该化合物选自结构式1/2及其盐、酯、溶剂合物、同位素异构体:
AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途,该化合物选自结构式1/2及其盐、酯、溶剂合物、同位素异构体。
其中,R1、R2、R3、R4、R5、R8、R9、R10的定义如专利申请PCT/CN2020/089692,公开号WO20 20228685A1中的权利要求书所记载。具体如下:
其中,
R1是C6-C10芳基或Z取代的芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、7-15元的稠环或Z取代稠环;
R2是氢、卤素原子、氰基或异氰基、羟基、巯基、胺基、OTs、OMS、C1-C6烷基或Z 取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、 1-6个碳原子的醚或Z取代的1-6个碳原子的烷氧基、-CONR6R7、-SO2NR6R7、-SO2R6、 -OCOO-R6、-COOR6、-NR6COR7、-OCOR6、-NR6SO2R7、-NR6SO2NR6R7或者R2和与其所键结的R1基团上的原子一起形成7-15元的稠环或Z取代稠环;
R3是氢、卤素、氰基或异氰基、羟基、巯基、胺基、OTs、OLCMS、C1-C6烷基或Z 取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、 C1-C6烷氧基或Z取代的C1-C6烷氧基、-CONR6R7、-SO2NR6R7、-SO2R6、-OCO-R6、-OCOO-R6、 -COOR6、-NR6COR7,-OCOR6、-NR6SO2R7;
R4、R5各自独立地是氢、卤素原子、氰基或异氰基、羟基、巯基、胺基、OTs、OLCMS、C1-C6烷基或Z取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C1-C6烷氧基或Z取代的C1-C6烷氧基、-CONR6R7、-SO2NR6R7、-SO2R6、 -OCOO-R6、-COOR6、-NR6COR6、-OCOR6、-NR6SO2R7或者R4、R5和与其所键结的苯环上的原子一起形成7-15元的稠环或Z取代稠环;
R6和R7各自独立地是氢、氰基或异氰基、C1-C6烷基或Z取代烷基、C2-C6烯基或Z 取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C1-C6烷氧基或Z取代的C1-C6烷氧基,或者R6、R7基团与其所键结的原子一起形成5-7元杂环基或Z取代5-7 元杂环基;
R8、R10各自独立地为氢、氘、芳基或Z取代芳基、C1-C6烷基或Z取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基且必有一个为氢、氘;
R9为至少具有一个氟原子或硝基取代的取代C6-C10芳基、至少具有一个氟原子或硝基取代的取代4-15元杂环、至少具有一个氟原子或硝基取代的取代5-15元杂芳基。
Z取代基为卤素原子、氰基或异氰基、羟基、巯基、胺基、OTs、OMS、C1-C3烷基或取代烷基、C1-C3烷氧基或取代烷氧基、C2-C3烯基或取代烯基、C2-C3炔基或取代炔基、C3-C8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环,取代的方式为单取代或偕二取代;
R9中的取代C6-C10芳基、取代4-15元杂环、取代5-15元杂芳基的取代基为卤素原子、硝基、氰基或异氰基、羟基、胺基、C1-C3烷基或烷氧基、烯基、炔基、环烷基或苯环、取代苯环、C1-C3烷氧基或卤原子取代烷氧基。
具体的,式(1)(2)的化合物选自:
具体定义和含义以及制备方法、波谱数据参见专利申请PCT/CN2020/089692,公开号WO20 20228685A1,在此将该申请全文引入。
显然结构式1/2的化合物与AST-3424、AST相同,都是AST-2660的前药,其会在AKR1C3酶的作用下活化而产生AST-2660(一种DNA烷化剂)发挥抗癌效果:
治疗方法,其使用含有含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者,该化合物选自结构式3及其盐、酯、溶剂合物、同位素异构体:
AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途,该化合物选自结构式3及其盐、酯、溶剂合物、同位素异构体:
其中,A、E、G、X、Y的定义如专利申请PCT/NZ2019/050030,公开号WO2019190331A1(对应中国申请号2019800234236,公开号CN111918864A)中的权利要求书所记载。具体如下:
其中:
A为H、C1-C6烷基、C1-C6烯基、C1-C6炔基、CFH2、CF2H、CF3、F、Cl、Br、I、OCF3、 COR或CON(R)2;
E为SO或SO2;
X为Cl、Br、I或OSO2R;
Y为Cl、Br、I或OSO2R;
每个R独立地为H或C1-C6烷基;
G是选自包括式(B)-(AA)的组中的自由基:
其中:
R1为H、C1-C6烷基、CH2(CH2)nOH、CH2CH(OH)CH2OH、苯基、吡啶基、苄基或吡啶基甲基,条件是当R1为苯基、吡啶基、苄基或吡啶基甲基时,R1任选地在任何可用位置处被C1- C6烷基、C1-C6烯基、C1-C6炔基、OR6、N(R6)(R7)、CFH2、CF2H、CF3、F、Cl、Br、I、OC F3、COR6、CON(R6)(R7)、SOR6、SON(R6)(R7)、SO2R6、SO2N(R6)(R7)、CN或NO2取代;
R2和R3各自独立地为H、C1-C6烷基、C1-C6烯基、C1-C6炔基、OR6、N(R6)(R7)、CFH2、CF2H、CF3、F、Cl、Br、I、OCF3、COR6、CON(R6)(R7)、SOR6、SON(R6)(R7)、SO2R6、SO2 N(R6)(R7)、CN或NO2;
R4为N(R6)(R7)、OH、OCH2(CH2)nN(R6)(R7)或CH2(CH2)nN(R6)(R7);
R5为H或C1-C6烷基基团;
R6和R7各自独立地为H或C1-6烷基,或者R6和R7一起形成取代或未被取代的5元或6元杂环;
Z为CH或N;
W为CH2、O、S、SO或SO2;
n为0至6;
*表示与式(I)的连接点。
具体的,式(3)的化合物选自:
具体定义和含义以及制备方法、波谱数据参见专专利申请PCT/NZ2019/050030,公开号WO 2019190331A1(对应中国申请号2019800234236,公开号CN111918864A),在此将该申请全文引入。
治疗方法,其使用含有含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者,该化合物选自结构式4及其盐、酯、溶剂合物、同位素异构体:
AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途,该化合物选自结构式4及其盐、酯、溶剂合物、同位素异构体:
其中,Rw的定义如专利申请PCT/CN2020/120281,公开号WO2021068952A1中的权利要求书所记载。具体如下:
R1为H、C1-6烷基、C3-6环烷基、4-6元杂环烷基、5-6元杂芳基或苯基,其中所述C1-6烷基、C3-6环烷基、4-6元杂环烷基、5-6元杂芳基和苯基任选被1、2或3个Ra所取代;
各Ra独立地为H、F、Cl、Br、I、-CN、-OH、C1-3烷氧基或C1-3烷基;
R2为H或C1-6烷基;
或者R1和R2连接在一起,与其相连的N原子一起形成4-6元杂环烷基,其中所述4-6元杂环烷基任选被1、2或3个Rb所取代;
各Rb独立地为H、F、Cl、Br、I、-CN、-OH、-NH2、-OCH3、-OCH2CH3、-CH3或-CH2 CH3;
R3为H、F、Cl、Br、I、-OH、-NH2、C1-3烷氧基或C1-3烷基;
T1为-(CRcRd)m-或-(CRcRd)n-O-;
m为1、2或3;
n为1或2;
T2为N或CH;
Rc和Rd各自独立地为H、F、C1-3烷基或C1-3烷氧基;
R4、R5和R6各自独立地为H、F、Cl、Br、I、C1-3烷基或C1-3烷氧基;
T为N或CH;
R7和R8各自独立地为H、F、Cl、Br或I;
R9和R10各自独立地为H、F、Cl、Br、I、-CN或
所述4-6元杂环烷基和5-6元杂芳基各自包含1、2、3或4个独立选自N、-O-和-S-的杂原子。
具体的,式(4)的化合物选自:
具体定义和含义以及制备方法、波谱数据参见专利申请PCT/CN2020/120281,公开号WO20 21068952A1,在此将该申请全文引入。
显然结构式3的化合物与AST-3424、AST相同,都是AST-2660的前药,其会在AKR1C3酶的作用下活化而产生AST-2660(一种DNA烷化剂)发挥抗癌效果:
治疗方法,其使用含有含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者,该化合物选自结构式5及其盐、酯、溶剂合物、同位素异构体:
AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途,该化合物选自结构式5及其盐、酯、溶剂合物、同位素异构体:
其中,X、Y、Z、R、T、A以及X10的定义如专利申请PCT/US2016/062114,公开号WO201708 7428A1(对应中国申请号2016800200132,公开号CN108136214A)中的权利要求书所记载。具体如下:
X10是O、S、SO或SO2;
A是C6-C10芳基、5-15元杂芳基或-N=CR1R2;
R1及R2各自独立是氢、C1-C6烷基、C3-C8环烷基、C6-C10芳基、4-15元杂环、醚、-CONR13R14或-NR13COR14;
X、Y及Z各自独立是氢、CN、卤基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、醚、-CONR13R14或-NR13COR14;
R是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、醚、-CONR13R14或-NR13COR14;
R13及R14各自独立是氢、C1-C6烷基、C3-C8环烷基、C6-C10芳基、4-15元杂环或醚
T包含胺基磷酸酯烷化剂,所述胺基磷酸酯烷化剂包含一或多个键结至-O-P(Z1)部分的 Z5-X5-Y5部分的烷化剂,其中Z5是包含氮、硫或氧的杂原子,X5是经取代或未经取代的伸乙基, Y5是卤基或另一离去基,或Z5-X5-Y5一起形成氮丙啶基(NCH2CH2)部分且Z1是O或S;且
其中这些烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基经取代或未经取代。
具体的,式(5)的化合物选自:
具体定义和含义以及制备方法、波谱数据参见专利申请PCT/US2016/062114,公开号WO20 17087428A1(对应中国申请号2016800200132,公开号CN108136214A),在此将该申请全文引入。
显然结构式5的化合物与AST-3424、AST类似,是胺基磷酸酯烷化剂的前药,其会在A KR1C3酶的作用下活化而产生T(一种胺基磷酸酯烷化剂,AST-2660就是一种胺基磷酸酯烷化剂)发挥抗癌效果:
治疗方法,其使用含有含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者,该化合物选自结构式6及其盐、酯、溶剂合物、同位素异构体:
AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途,该化合物选自结构式6及其盐、酯、溶剂合物、同位素异构体:
其中:
A是取代或未经取代的C6-C10的芳基、联芳基或取代的联芳基、5-15元的杂芳基或-N=C R1R2,其中取代时的取代基选自由以下组成的群:卤基、-CN、-NO2、–O-(CH2)-O-、-CO2H及其盐、-OR100、-CO2R100、-CONR101R102、-NR101R102、-NR100SO2R100、-SO2R100、-SO2NR101R102、C1-C6烷基、C3-C10杂环基;
其中,R100、R101及R102各自独立是氢、C1-C8烷基、C6-C12芳基;或R101及R102与其附接至的氮原子一起形成5-7元杂环;
其中烷基及芳基各自是经1-3个卤基或1-3个C1-C6烷基取代;
R1及R2各自独立是苯基或甲基;
X、Y及Z各自独立是氢或卤基;
R是氢或C1-C6烷基或卤素取代烷基。
“化合物”也当然包括化合物本身以及该化合物的溶剂合物、盐、酯或同位素异构体等。
基团前的“Cx-Cy”或“Cx-y”是指存在于该基团中的碳原子数目的范围。举例而言,C1-C6 烷基是指具有至少1个且最多6个碳原子的烷基。
“烷基”是指具有1至10个碳原子且在一些实施例中具有1至6个碳原子的单价饱和脂肪族烃基。“Cx-y烷基”是指具有x至y个碳原子的烷基。此术语包括(举例而言)直链及具支链烃基,例如甲基(CH3-)、乙基(CH3CH2-)、正丙基(CH3CH2CH2-)、异丙基((CH3)2CH-)、正丁基 (CH3CH2CH2CH2-)、异丁基((CH3)2CHCH2-)、仲丁基((CH3)(CH3CH2)CH-)、叔丁基((CH3)3C-)、正戊基(CH3CH2CH2CH2CH2-)及新戊基((CH3)3CCH2-)。
“芳基”是指具有6至14个碳原子且不含环杂原子且具有单环(例如,苯基)或多个缩合(稠合)环(例如,萘基或蒽基)的芳香族基团。对于包括不具有环杂原子的具有芳香族环及非芳香族环的稠合、桥连及螺环系统的多环系统而言,当附接点位于芳香族碳原子处时,术语“芳基”或“Ar”适用(例如,5,6,7,8四氢萘-2-基是芳基,此乃因其附接点是位于芳香族苯基环的2 位处)。“伸芳基”是指具有适当氢含量的二价芳基。
“环烷基”是指具有3至14碳原子且没有环杂原子且具有单环或包括稠合、桥连及螺环系统的多环的饱和或部分饱和环状基团。对于不具有环杂原子的具有芳香族及非芳香族环的多环系统而言,当附接点是位于非芳香族碳原子处时,术语“环烷基”适用(例如5,6,7,8-四氢萘 -5-基)。术语“环烷基”包括环烯基。环烷基的实例包括(例如)金刚烷基、环丙基、环丁基、环戊基、环辛基及环己烯基。“伸环烷基”是指具有适当氢含量的二价环烷基。
“卤基”是指氟、氯、溴及碘中的一或多者。
“杂芳基”是指具有1至14个碳原子及1至6个选自由氧、氮及硫组成的群的杂原子的芳香族基团且包括单环(例如咪唑基-2-基及咪唑-5-基)及多环系统(例如咪唑并吡啶基、苯并三唑基、苯并咪唑-2-基及苯并咪唑-6-基)。对于包括具有芳香族及非芳香族环的稠合、桥连及螺环系统的多环系统而言,若存在至少一个环杂原子且附接点是位于芳香族环的原子处,则应用术语“杂芳基”(例如1,2,3,4-四氢喹啉-6-基及5,6,7,8-四氢喹啉-3-基)。在一些实施例中,杂芳基的氮及/或硫环原子视情况经氧化以提供N-氧化物(N→O)、亚磺酰基或磺酰基部分。术语杂芳基包括(但不限于)吖啶基、吖辛因基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基(benzothiophenyl)、苯并恶唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并噻吩基(benzothienyl)、苯并咪唑啉基、咔唑基、NH- 咔唑基、咔啉基、苯并二氢吡喃基(chromanyl)、苯并吡喃基(chromenyl)、噌啉基(cinnolinyl)、二噻嗪基、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑并吡啶基、咪唑基、吲唑基、二氢吲哚基(indolenyl)、吲哚啉基、吲嗪基、吲哚基、异苯并呋喃基、异苯并二氢吡喃基 (isochromanyl)、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基(isoquinolinyl)、异喹啉基 (isoquinolyl)、异噻唑基、异恶唑基、萘啶基、八氢异喹啉基、恶二唑基、恶唑啶基、恶唑基、嘧啶基、啡啶基、啡啉基、吩嗪基、吩噻嗪基、吩恶噻基、吩恶嗪基、酞嗪基、六氢吡嗪基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑啶基、吡唑啉基、吡唑基、嗒嗪基、吡啶并恶唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喏啉基、奎宁环基、四氢异喹啉基、四氢喹啉基、四唑基、噻二嗪基、噻二唑基、噻蒽基、噻唑基、噻吩基(thienyl)、噻吩并噻唑基、噻吩并恶唑基、噻吩并咪唑基、噻吩基(thiophenyl)、三嗪基及呫吨基。“伸杂芳基”是指具有适当氢含量的二价杂芳基。
“杂环状”或“杂环”或“杂环烷基”或“杂环基”是指具有1至14个碳原子及1至6个选自由氮、硫或氧组成的群的杂原子的饱和或部分饱和环状基团且包括单环及包括稠合、桥连及螺环系统的多环系统。对于具有芳香族及/或非芳香族环的多环系统而言,当存在至少一个环杂原子且附接点是位于非芳香族环的原子处时,术语“杂环状”、“杂环”、“杂环烷基”或“杂环基”适用(例如1,2,3,4-四氢喹啉-3-基、5,6,7,8-四氢喹啉-6-基及十氢喹啉-6-基)。在一些实施例中,此处杂环基是3-15元、4-14元、5-13元、7-12或5-7元杂环。在一些其他实施例中,杂环含有4个杂原子。在一些其他实施例中,杂环含有3个杂原子。在另一实施例中,杂环含有最多2个杂原子。在一些实施例中,杂环基的氮及/或硫原子视情况经氧化以提供N- 氧化物、亚磺酰基、磺酰基部分。杂环基包括(但不限于)四氢吡喃基、六氢吡啶基、N-甲基六氢吡啶-3-基、六氢吡嗪基、N-甲基吡咯啶-3-基、3-吡咯啶基、2-吡咯啶酮-l-基、吗啉基及吡咯啶基。指示碳原子数的前缀(例如,C3-10)是指杂环基部分中除杂原子数之外的总碳原子数。二价杂环基将具有适当调整的氢含量。
“联芳基”是指两个芳环通过C-C单键相联的结构,如联苯、联吡啶等。
术语“视情况经取代”是指经取代或未经取代的基团。基团可经一或多个取代基(例如1、 2、3、4或5个取代基)取代。较佳地,取代基选自由以下组成的群:侧氧基、卤基、-CN、NO2、 -N2+、-CO2R100、-OR100、-SR100、-SOR100、-SO2R100、-NR100SO2R100、-NR101R102、-CONR101R102、-SO2NR101R102、 C1-C6烷基、C1-C6烷氧基、-CR100=C(R100)2、-CCR100、C3-C10环烷基、C3-C10杂环基、C6-C12芳基及C2-C12杂芳基或诸如–O-(CH2)-O-、–O-(CH2)2-O-及其1-4个甲基经取代的形式等二价取代基,其中 R100、R101及R102各自独立是氢或C1-C8烷基;C3-C12环烷基;C3-C10杂环基;C6-C12芳基;或C2-C12杂芳基;或R101及R102与其附接至的氮原子一起形成5-7元杂环;其中烷基、环烷基、杂环基、芳基或杂芳基各自视情况经1-3个卤基、1-3个C1-C6烷基、1-3个C1-C6卤烷基或1-3个C1-C6烷氧基取代。较佳地,取代基选自由以下组成的群:氯、氟、-OCH3、甲基、乙基、异丙基、环丙基、-CO2H 及其盐及C1-C6烷基酯、CONMe2、CONHMe、CONH2、-SO2Me、-SO2NH2、-SO2NMe2、-SO2NHMe、-NHSO2Me、 -NHSO2CF3、-NHSO2CH2Cl、-NH2、-OCF3、-CF3及-OCHF2。
具体的,式(6)的化合物选自:
具体定义和含义以及制备方法、波谱数据参见PCT/US2016/021581,公开号WO2016145092 A1(对应中国申请号2016800150788,公开号CN107530556A);PCT/US2016/062114,公开号W O2017087428A1(对应中国申请号2016800200132,公开号CN108136214A);PCT/CN2020/0896 92,公开号WO2020228686所公开,在此将这些申请全文引入。
显然结构式6的化合物与AST-3424、AST类似,是AST-2660的前药,其会在AKR1C3酶的作用下活化而产生AST-2660发挥抗癌效果:
AST-3424(OBI-3424)、(以下代号为AST)以及/>的合成方法、波谱数据被专利申请:PCT/US2016/021581,公开号WO2016145092A1,对应中国申请号2016800150788,公开号CN107530556A;PCT/US2016/062114,公开号WO2017087428A1,对应中国申请号2016800200132,公开号CN108136214A;PCT/CN2020/089692,公开号WO2020228 686所公开;相关的制剂浓缩注射液,并且相关处方、制备方法和临床配伍、施用方法被相关专利:WO2021008520A1、WO2021043275A1所详细说明并公开,在此本发明将上述申请文本的全文引入。
单药,即单药治疗。联用,即联合用药治疗。单药治疗是指在一个疗程中仅使用一种抗癌药物。联合治疗是指在一个疗程中同时或先后使用两种或两种以上的抗癌药物。
一般而言,联合治疗需要根据病情特点、联用药物种类探索不同的给药剂量、给药周期,只有根据上述情况,探索得到的联合用药治疗方案才可能取得较单一用药治疗好的治疗效果。
单药和联用治疗方案的药物给药剂量、给药周期均需要在参考上述AST-3424及其类似化合物和其他药物的剂量、给药方案通过临床试验探索得到。
单药可以参考WO2019062919A1以及WO2016145092A1、WO2017087428A1的动物实验剂量来确定给药剂量。
进一步,KRAS突变选自KRAS-G12D突变、KRAS-G12V突变和KRAS-G12C突变。
KRAS对应的基因中的任意一个基因突变或两个基因突变可以通过市售的(伴随)诊断试剂盒进行检测诊断,比如在中国获批的诊断试剂盒:
厦门艾德生物Amoy Dx,国械注准20153401126,人类KRAS基因突变检测试剂盒(荧光PCR法)
上海透景生命,国械注准20163401341,人K-RAS基因7种突变检测试剂盒(PCR荧光法)。
当然也可以使用NGS测序(YS 450基因NGS大panel)来判定具体的KRAS突变亚型。
更优选的,KRAS突变选自KRAS-G12D突变。
所述的基因突变的TMB(肿瘤基因突变负荷)水平为中。
由于不同瘤种之间TMB(Tumor mutation load(burden)即肿瘤基因突变负荷)高低不同:一般认为:TMB超过20个突变/Mb(Mb代表的就是每百万个碱基),就是高;低于1 0个突变/Mb,就是低,处于中间的就是中。2017年世界肺癌大会上,施贵宝公司公布过一项名为CheckMate-032的临床试验结果。这是一项纳入了401名一线治疗失败的晚期肺癌患者的II期临床试验,接受PD-1抑制剂单独或联合伊匹木治疗。按照TMB高低划分成TMB高、 TMB中、TMB低三类病人,那么在接受联合治疗的人群中,三组的有效率分别为62%、20%、 23%,TMB高的人群有效率高3倍;而三组的中位总生存期,分别为:22.0个月、3.6个月、 3.4个月——22.0个月与3.4个月,相差6倍!该试验证明,对于不同的癌症治疗药物,不同的 TMB水平对于药物的疗效有很大的影响。
进一步,前药化合物优选自:
其他治疗药物选自KRAS抑制剂、免疫治疗药物(免疫检查点抑制剂)。
KRAS抑制剂即抑制KRAS酶活性的物质。具体可以参考综述文献Goebel,Lisa&Müller, Matthias&Goody,Roger&Rauh,Daniel.(2020).KRasG12C inhibitors in clinicaltrials:A short historical perspective.RSC Medicinal Chemistry.11.10.1039/D0MD00096E.
进入临床开发或已经上市的KRAS抑制剂包括美国安进开发的Sotorasib(AMG510)、Mirat i Therapeutics开发的adagrasib(MRTX849)、罗氏开发的GDC6036、礼来开发的LY3499446、 Araxes和Janssen联合开发的JNJ74699157(ARS3248)、益方生物开发的D-1553、加科思开发的J AB-3312、加科思开发的JAB-3068、勤浩医药(Gen House)开发的GH35、贝达药业开发的B PI-421286、勃林格殷格翰开发的BI17016963、Moderna开发的mRNA-5671、阿斯利康与Ionis 公司合作开发的AZD-4785。
其中,KRAS抑制剂选自Sotorasib(AMG510)、adagrasib(MRTX849)、GDC6036、LY3499446、JNJ74699157(ARS3248)、D-1553;
免疫检查点分子(immune cheeckpoint)是免疫系统中起抑制作用的调节分子,其对于维持自身耐受、防止自身免疫反应、以及通过控制免疫应答的时间和强度而使组织损伤最小化等至关重要。免疫检查点分子表达于免疫细胞上,将抑制免疫细胞功能,使机体无法产生有效的抗肿瘤免疫应答,肿瘤形成免疫逃逸。与肿瘤相关的免疫检查点分子主要有:P D1、PD-L1、CTLA4、Tim3和LAG3等,目前研究较多的为PD1、PD-L1、CTLA4。免疫检查点抑制剂就是针对相应的免疫检查点研发的一些单抗类药物,其主要作用为阻断表达免疫检查点的肿瘤细胞与免疫细胞之间的作用,从而阻断肿瘤细胞对免疫细胞的抑制作用。免疫治疗药物选自PD-1单抗、PD-L1单抗。
所述癌症、肿瘤优选自胃癌、胰腺癌、肺癌。
上述药物除含有对应的前药化合物外,还应根据药品、药物、制剂的特定,添加药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型,例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式,所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种:稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
附图说明
图13为三个PDX模型肿瘤组织及对照组的IHC染色结果照片。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解,这些实施例仅用于说明本发明,其不以任何方式限制本发明的范围。
向患者“投与”(“administering”或“administration of”)药物(及此词组的语法等效形式)是指直接投与(其可由医学专业人士向患者投与或可自投与)及/或间接投与,其可是开处药物的行为。举例而言,指示患者自投与药物及/或将药物的处方提供给患者的医师是向患者投与药物。
“癌症”是指可通过侵袭而局部扩展且通过转移而全身扩展的潜在无限制生长的白血病、淋巴瘤、癌及其他恶性肿瘤(包括实体肿瘤)。癌症的实例包括(但不限于)肾上腺、骨、脑、乳房、支气管、结肠及/或直肠、胆囊、头及颈、肾、喉、肝、肺、神经组织、胰脏、前列腺、副甲状腺、皮肤、胃及甲状腺的癌症。癌症的某些其他实例包括急性及慢性淋巴细胞及粒细胞肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈上皮分化不良及原位癌、尤文氏肉瘤(Ewing’ssarcoma)、表皮样癌、巨细胞瘤、多型性神经胶母细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西肉瘤(Kaposi’s sarcoma)、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性黑色素瘤、恶性高钙血症、马方样体型肿瘤(marfanoid habitustumor)、髓样上皮癌、转移性皮肤癌、黏膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性及其他肉瘤、卵巢瘤、嗜铬细胞瘤、真性红血球增多症、原发性脑瘤、小细胞肺癌、溃疡型及乳头型二者的鳞状细胞癌、增生、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病灶、网状细胞肉瘤及威尔姆氏肿瘤(Wilm’s tumor)。
“患者”及“个体”可互换使用,是指需要癌症治疗的哺乳动物。通常,患者是人类。通常,患者是诊断患有癌症的人类。在某些实施例中,“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物,例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“实体肿瘤”是指包括(但不限于)骨、脑、肝、肺、淋巴结、胰脏、前列腺、皮肤及软组织(肉瘤)中的转移肿瘤的实体肿瘤。
药物的“治疗有效量”是指当向患有癌症的患者投与时,将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与一个剂量而出现,且可仅在投与一系列剂量后出现。因此,治疗有效量可以一或多次投与来投与。
病况或患者的“治疗”(“Treating”、“treatment of”或“therapy of”)是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的,有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善;疾病程度的减弱;疾病进展的延迟或减缓;疾病状态的改善、缓解或稳定;或其他有益结果。在一些情形下,癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如,哺乳动物,例如鼠类、犬、猫、马或人类)的肿瘤细胞。
“患者”及“个体”可互换使用,是指需要癌症治疗的哺乳动物。通常,患者是人类。通常,患者是诊断患有癌症的人类。在某些实施例中,“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物,例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“治疗”或“治疗患者”是指向患者投与、使用或施用本发明相关的治疗有效量的药物。
向患者“投与”或“施用”“使用”药物是指直接投与或施用(其可由医学专业人士向患者投与或施用或者可自投与或施用)及/或间接投与或施用,其可是开处药物的行为。举例而言,指示患者自投与或施用药物及/或将药物的处方提供给患者的医师是向患者投与或施用药物。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的,有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善;疾病程度的减弱;疾病进展的延迟或减缓;疾病状态的改善、缓解或稳定;或其他有益结果。在一些情形下,癌症的治疗可使得部分反应或稳定疾病。
下述实施例中的实验方法,如无特殊说明,均为常规方法。所用的药材原料、试剂材料等,如无特殊说明,均为市售购买产品。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明所附权利要求的范围。
以下提供本发明的具体实验。
胃癌GA6201PDX模型是带有G12D氨基酸突变的KRAS致病突变(KRAS-G12D)的模型。BALB/c裸小鼠皮下接种/>模型GA6201瘤块,建立人胃癌皮下移植肿瘤模型。试验分为测试药Ifosfamide(异环磷酰胺)60mg/kg组、测试药AST-34245mg/kg 组、AST 2.5mg/kg和5mg/kg组及生理盐水(pH 7.0-7.6)溶媒对照组,共5组,每组5只小鼠。其中,生理盐水(pH 7.0-7.6)溶媒对照组、测试药AST-34245mg/kg、AST 2.5mg/ kg和5mg/kg组是尾静脉注射给药,每周给药一次,共给药三周,观察四周。Ifosfamide 60 mg/kg组腹腔注射给药,每周连续给五天停两天,共给药两周,观察五周。根据相对肿瘤抑制率TGI(%)进行疗效评价,根据动物体重变化和死亡情况进行安全性评价。
具体每一组的该药方案下表1所示。
分别在不同天数对不同组别的小鼠的肿瘤体积进行测量,并取得平均值,其结果如下表2 所示。
根据表2的数据制作体现各治疗组和对照组肿瘤生长情况的图2。
根据表2的数据制作药效评估分析数据,具体数据见表3。
表3中相对肿瘤增殖率,T/C%,即在某一时间点,治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下:
T/C%=TRTV/CRTV×100%(TRTV:治疗组平均RTV;CRTV:溶媒对照组平均 RTV;RTV=Vt/V0,V0为分组时该动物的瘤体积,Vt为治疗后该动物的瘤体积);
相对肿瘤抑制率,TGI(%),计算公式如下:TGI%=(1-T/C)×100%。(T和C分别为治疗组和对照组在某一特定时间点的平均相对肿瘤体积(RTV)。
Group | 0 | 1 | 2 | 3 | 4 | 7 | 8 | 9 | 10 | 1114 | 15 | 16 | 17 | 18 | 21 | 24 | 28 | 31 | 35 | 38 |
Group 01 | 25.3 | 25.4 | 25.3 | 24.4 | 25.4 | 24.6 | 23.8 | 24.3 | 23.7 | 24.0 | 24.4 | 25.1 | ||||||||
Group 02 | 2.58 | 25.5 | 25.0 | 25.5 | 24.4 | 24.4 | 24.5 | 24.1 | 24.4 | 24.424.3 | 25.1 | 26.3 | 26.1 | 25.5 | 25.2 | 26.0 | 26.2 | |||
Group 03 | 24.8 | 25.1 | 25.1 | 24.5 | 25.4 | 25.0 | 25.5 | 25.6 | 25.3 | 25.4 | 25.7 | 26.0 | ||||||||
Group 04 | 25.0 | 24.4 | 24.8 | 24.5 | 25.2 | 24.9 | 25.4 | 25.1 | 24.6 | 25.2 | 25.6 | 25.7 | ||||||||
Group 05 | 25.3 | 25.1 | 25.0 | 25.0 | 25.2 | 24.9 | 25.4 | 25.8 | 25.0 | 25.4 | 25.6 | 25.4 |
将上表4制作为曲线图,可以得到图2。
分别在不同天数对不同组别的小鼠的体重进行测量,并取得平均值,其结果如下表5所示。
Group | 0 | 1 | 2 | 3 | 4 | 7 | 8 | 9 | 10 | 1114 | 15 | 16 | 17 | 18 | 21 | 24 | 28 | 31 | 35 | 38 |
Group 01 | 25.3 | 25.4 | 25.3 | 24.4 | 25.4 | 24.6 | 23.8 | 24.3 | 23.7 | 24.0 | 24.4 | 25.1 | ||||||||
Group 02 | 25.8 | 25.5 | 25.0 | 25.5 | 24.4 | 24.4 | 24.5 | 24.1 | 24.4 | 24.424.3 | 25.1 | 26.3 | 26.1 | 25.5 | 25.2 | 26.0 | 26.2 | |||
Group 03 | 24.8 | 25.1 | 25.1 | 24.5 | 25.4 | 25.0 | 25.5 | 25.6 | 25.3 | 25.4 | 25.7 | 26.0 | ||||||||
Group 04 | 25.0 | 24.4 | 24.8 | 24.5 | 25.2 | 24.9 | 25.4 | 25.1 | 24.6 | 25.2 | 25.6 | 25.7 | ||||||||
Group 05 | 25.3 | 25.1 | 25.0 | 25.0 | 25.2 | 24.9 | 25.4 | 25.8 | 25.0 | 25.4 | 25.6 | 25.4 |
同理对表5的数据进行处理可以得到下表6。
表6:胃癌GA6201模型中不同接种天数小鼠的体重变化百分比(%GroupMean Change=mean((T-T0)/T0)*100,T表示current value,T0表示initial value)
上表4/5/6中的Group01、Group02、Group03、Group04、Group05即上述的第1组、第2组、第3组、第4组、第5组、第6组。0/1/2/3/4/7/8/9/10/11/14/15/16/17/18/21/24/28/31/35/38 是接种后的天数。
将上表制作为曲线图,可以得到图4。
分析实验数据可知,疗效方面:
测试药AST-3424在5mg/kg剂量下,测试药AST在2.5mg/kg和5mg/kg剂量下,对H胃癌GA6201具有显著抑制肿瘤生长的作用,相较对照组统计学上均有显著性差异。测试药Ifosfamide在60mg/kg剂量下,对/>胃癌GA6201具有一定的抑制肿瘤生长的作用,但相较对照组统计学上均无显著性差异。
分析实验数据可知,荷瘤小鼠对Ifosfamide、AST-3424、AST在测试剂量下耐受良好。
胰腺癌PA1222PDX模型是带有G12D氨基酸突变的KRAS致病突变(KRAS -G12D)的模型。BALB/c裸小鼠皮下接种/>模型PA1222瘤块,建立人胰腺癌皮下移植肿瘤模型。试验分为测试药Gemcitabine(吉西他滨)120mg/kg组、测试药AST 10mg/kg 及7.5%无水乙醇+7.5%聚氧乙烯(35)蓖麻油+85%葡萄糖注射液D5W(pH7.4)溶媒对照组,共3组,每组5只小鼠。其中,7.5%无水乙醇+7.5%聚氧乙烯(35)蓖麻油+85%葡萄糖注射液D5W(pH7.4)溶媒对照组、测试药AST 10mg/kg组是尾静脉注射给药,每周给药一次,连续给药三周。测试药Gemcitabine 120mg/kg组腹腔注射给药,每周给药一次,连续给药3 周。根据相对肿瘤抑制率TGI(%)进行疗效评价,根据动物体重变化和死亡情况进行安全性评价。
具体每一组的该药方案下表7所示。
注:1.给药体积为10μl/g
2.QW×3;每周给药一次,给药三周
分别在不同天数对不同组别的小鼠的肿瘤体积进行测量,并取得平均值,其结果如下表8 所示。
各治疗组和对照组肿瘤生长情况见表8和图5,药效评估见表9。
表9:相对肿瘤增殖率,T/C%,即在某一时间点,治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下:
T/C%=TRTV/CRTV×100%(TRTV:治疗组平均RTV;CRTV:溶媒对照组平均 RTV;RTV=Vt/V0,V0为分组时该动物的瘤体积,Vt为治疗后该动物的瘤体积);
相对肿瘤抑制率,TGI(%),计算公式如下:TGI%=(1-T/C)×100%。(T和C分别为治疗组和对照组在某一特定时间点的平均相对肿瘤体积(RTV)。
将上表制作为曲线图,可以得到图6。
分别在不同天数对不同组别的小鼠的体重进行测量,并取得平均值,其结果如下表11所示。
Group | 0 | 3 | 7 | 10 | 14 | 17 | 21 | 24 | 28 |
Group 01 | 24.0 | 24.1 | 24.6 | 24.6 | 24.4 | 24.3 | 25.1 | 24.8 | 25.0 |
Group 02 | 24.1 | 23.9 | 24.4 | 24.3 | 24.6 | 24.2 | 25.1 | 25.1 | 25.4 |
Group 03 | 24.0 | 23.5 | 24.0 | 23.6 | 23.6 | 23.6 | 24.0 | 24.0 | 24.1 |
同理对表11的数据进行处理可以得到下表12。
表12:胰腺癌PA1222模型中不同接种天数小鼠的体重变化百分比(%Group mean Change=mean((T-T0)/T0)*100,T表示current value,T0表示initialvalue)
将上表制作为曲线图,可以得到图8。
分析实验数据可知,疗效方面:
测试药Gemcitabine在120mg/kg(Group 2)剂量下,对胰腺癌PA1222具有一 定的抑制肿瘤生长的作用,相较对照组统计学上有显著性差异。测试药AST在10mg/kg(Gr oup 3)剂量下,对/>胰腺癌PA1222有显著的抑瘤作用,相较对照组统计学上有显著 性差异,并且该组有两只小鼠肿瘤被治愈,治愈率均为40%。测试药AST 10mg/kg(Group 3) 的抑瘤效果显著优于测试药Gemcitabine(120mg/kg,Group 2)(p=0.000778)。
分析实验数据可知,测试药Gemcitabine(120mg/kg,Group 2)治疗组、AST 10mg/kg (Group 3)治疗组以及对照组(Group 1)的小鼠没有任何明显的体重下降的现象,治疗期间耐受良好。
肺癌LU11693PDX模型是带有G12C氨基酸突变的KRAS致病突变的模型。BALB/c Nude裸小鼠皮下接种/>模型LU11693瘤块,建立人肺癌皮下移植肿瘤模型。试验分为测试药Cisplatin 4mg/kg组、测试药AST 10mg/kg组及7.5%无水乙醇+7.5%聚氧乙烯(35)蓖麻油+85%葡萄糖注射液D5W(pH7.4)溶媒对照组,共3组,每组6只小鼠,尾静脉注射给药,每周给药一次,连续给3周。根据相对肿瘤抑制率TGI(%)进行疗效评价,根据动物体重变化和死亡情况进行安全性评价。
具体每一组的该药方案下表13所示。
注:1.给药体积为10μl/g
2.QW×3;每周给药一次,给药三周
分别在不同天数对不同组别的小鼠的肿瘤体积进行测量,并取得平均值,其结果如下表1 4所示。
各治疗组和对照组肿瘤生长情况见表14和图9,药效评估见表1,5。
表15中,相对肿瘤增殖率,T/C%,即在某一时间点,治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下:
T/C%=TRTV/CRTV×100%(TRTV:治疗组平均RTV;CRTV:溶媒对照组平均 RTV;RTV=Vt/V0,V0为分组时该动物的瘤体积,Vt为治疗后该动物的瘤体积);
相对肿瘤抑制率,TGI(%),计算公式如下:TGI%=(1-T/C)×100%。(T和C分别为治疗组和对照组在某一特定时间点的平均相对肿瘤体积(RTV)。
将上表制作为曲线图,可以得到图10。
分别在不同天数对不同组别的小鼠的体重进行测量,并取得平均值,其结果如下表15所示。
Group | 0 | 4 | 7 | 11 | 14 | 18 | 21 | 25 | 28 |
Group 01 | 24.5 | 24.6 | 24.5 | 24.5 | 24.9 | 24.9 | 24.6 | 24.3 | 24.4 |
Group 02 | 24.3 | 23.6 | 23.9 | 22.8 | 24.0 | 22.4 | 23.0 | 23.4 | 23.6 |
Group 03 | 24.3 | 24.3 | 23.9 | 23.3 | 23.6 | 23.3 | 23.0 | 22.4 | 22.8 |
同理对表15的数据进行处理可以得到下表16。
表16:肺癌LU11693模型中不同接种天数小鼠的体重变化百分比(%Group Mean Change=mean((T-T0)/T0)*100,T表示current value,T0表示initialvalue)
Group | 0 | 4 | 7 | 11 | 14 | 18 | 21 | 25 | 28 |
Group 01 | 0.00% | 0.53% | 0.07% | 0.20% | 1.54% | 1.81% | 0.63% | -0.54% | -0.18% |
Group 02 | 0.00% | -2.95% | -1.68% | -6.23% | -1.32% | -8.04% | -5.33% | -3.86% | -2.74% |
Group 03 | 0.00% | 0.15% | -1.86% | -4.24% | -3.09% | -4.15% | -5.47% | -7.78% | -6.38% |
将上表制作为曲线图,可以得到图12。
分析实验数据可知,疗效方面:
测试药Cisplatin(4mg/kg)治疗组在首次给药后的第28天(Day28)表现出一定的抑瘤作用,相较对照组统计学上有显著性差异(p=0.0152),相对肿瘤抑制率TGI(%)为23.98%。
测试药AST(10mg/kg)治疗组在首次给药后的第28天(Day 28)表现出一定的抑瘤作用,相较对照组统计学上有显著性差异(p<0.001),相对肿瘤抑制率TGI(%)为54.64%,TGI小于60%,没有明显的抑瘤效果。
分析实验数据可知,测试药AST(10mg/kg)和Cisplatin(4mg/kg)治疗组有个别小鼠出现体重严重下降的现象,可能与高剂量药物潜在的毒性有关。
由上述三组实验数据我们可以得出以下结论:
1.AST-3424和AST在带有G12D氨基酸突变的KRAS致病突变模型:胃癌GA6021和胰腺癌PA1222 PDX模型中均具有显著的药效,TGI%均大于90%;
2.AST在带有G12C氨基酸突变的KRAS致病突变模型:肺癌LU11693中的抑瘤效果不明显,TGI%小于60%。
3.AST-3424和AST在各模型中均具有比较好的耐受性。
4、胃癌GA6021、胰腺癌PA1222、肺癌LU11693组织中的AKR1C3的RNA表达水平及酶含量的检测
A、AKR1C3 RNA表达水平FPKM检测
根据文献(Meng,F.,Li,W.F.,Jung,D.,Wang,C.C.,Qi,T.,Shia,C.S.,Hsu,R.Y.,Hsieh,Y.C.,&Duan,J.(2021).A novel selective AKR1C3-activated prodrug AST-3424/OBI -3424exhibits broad anti-tumor activity.American journal of cancerresearch,11(7),3645-36 59.)的记载方法,使用RNA-Seq分析了上述胃癌GA6021、胰腺癌PA1222、肺癌LU11693 组织中的AKR1C3的RNA表达水平(AKR1C3 RNA expression level,并使用Log2 FPKM 进行定量),结果如下:
GA6201检测得到AKR1C3 LOG2(FPKM)为6.78,LU11693为11.14,PA1222为7.39,参见表17。
根据上述文献,可知这三个肿瘤组织的AKR1C3 RNA均为高表达。
B、AKR1C3蛋白含量的IHC方法检测及H-SCORE打分
根据常用的IHC(免疫组织化学)染色法对这三个组织的AKR1C3蛋白含量进行测定(使用商用的IHC试剂,一抗为Abcam公司的兔抗体Rabbit IgG mAb,二抗为Leica公司的聚合物优化检测系统Bond Polymer Refine Detection,染色条件:抗原修复100℃,pH9.0EDTA 缓冲液20min,稀释比:1:800),并对染色结果进行H-SCORE打分:免疫组化染色强度将被分为0(阴性),1+(弱染色),2+(中染色),3+(强染色),人工在打分仪器上设置弱染色、中染色、强染色的阈值,然后通过图像处理软件对染色样本照片进行色彩识别,所有样品的染色照片按照统一的标准,由评分软件对某个细胞对应的染色情况进行评分: 0/1/2/3。并统计不同染色强度的阳性细胞数量占切片中总细胞数量的百分数。通过下面的公式计算H-Score作为每个样品的IHC结果评分。H-score得分将在0~300之间,评分越高则表示该抗体对应的靶点(AKR1C3酶蛋白)在该样品中表达量越高。计算公式如下:
H-Score=(%at 0)×0+(%at 1)×1+(%at 2)×2+(%at 3)×3
染色结果如图13,打分结果如下表17:
表17:三个模型及对照组的IHC和RNA分析检测结果
具体染色统计结果如下表18:
表18:三个模型及对照组的IHC结果及H-SCORE打分
上述染色结果中阳性和阴性对照结果在控制范围内即表明本次IHC染色剂H-SCORE打分结果是可信的。
根据上述结果可知,这三个组织对应的AKR1C3蛋白均为高表达。
综合以上三个PDX模型药效实验结果以及这三个模型使用的组织均为人AKR1C3高表达的肿瘤组织可知,AST-3424和AST对高表达AKR1C3且带有G12D氨基酸突变的KRAS致病突变的癌症具有显著的治疗效果,而对于高表达AKR1C3且带有G12C氨基酸突变的KRA S致病突变的癌症治疗效果不显著。
根据文献(Meng,F.,Li,W.F.,Jung,D.,Wang,C.C.,Qi,T.,Shia,C.S.,Hsu,R.Y.,Hsieh,Y.C.,&Duan,J.(2021).A novel selective AKR1C3-activated prodrug AST-3424/OBI -3424exhibits broad anti-tumor activity.American journal of cancerresearch,11(7),3645-36 59;Evans,K.,Duan,J.,Pritchard,T.,Jones,C.D.,McDermott,L.,Gu,Z.,Toscan,C.E., El-Zein,N.,Mayoh,C.,Erickson,S.W.,Guo,Y.,Meng,F.,Jung,D.,Rathi,K.S.,Roberts, K.G.,Mullighan,C.G.,Shia,C.S.,Pearce,T.,Teicher,B.A.,Smith,M.A.,…Lock,R. B.(2019).OBI-3424,a Novel AKR1C3-Activated Prodrug,Exhibits Potent Efficacy against Preclinical Models of T-ALL.Clinical cancerresearch:an official journal of the American Association for Cancer Research,25(14),4493-4503;Yanlan Wang,Yue Liu,Changhua Zhou, Chunnian Wang,Ning Zhang,Donglin Cao,Qing Li&Zhong Wang(2020)An AKR1C3-s pecific prodrug with potentanti-tumor activities against T-ALL,Leukemia&Lymphoma,61 (7),1660-1668。)以及对应的专利申请:
PCT/US2016/021581,公开号WO2016145092A1(对应中国申请号2016800150788,公开号CN107530556A),
PCT/US2016/062114,公开号WO2017087428A1(对应中国申请号2016800200132,公开号CN108136214A),
PCT/CN2020/089692,公开号WO2020228685A1;
PCT/NZ2019/050030,公开号WO2019190331A1(对应中国申请号2019800234236,公开号CN111918864A);
PCT/CN2020/120281,公开号WO2021068952A1,
因此,结合上述AST-3424、AST的实验结果,可以推测AKR1C3活化的DNA烷化剂前药对于单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者,特别是KRAS-G12D亚型突变的患者具有显著的治疗效果。
Claims (10)
1.治疗方法,其使用含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者。
2.治疗方法,其使用含有含有AKR1C3活化的DNA烷化剂前药化合物的药物单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者,该化合物选自结构式1/2/3/4/5/6及其盐、酯、溶剂合物、同位素异构体:
其中,R1、R2、R3、R4、R5、R8、R9、R10的定义如专利申请PCT/CN2020/089692,公开号WO2020228685A1中的权利要求书所记载;
其中,A、E、G、X、Y的定义如专利申请PCT/NZ2019/050030,公开号WO2019190331A1(对应中国申请号2019800234236,公开号CN111918864A)中的权利要求书所记载;
其中,Rw的定义如专利申请PCT/CN2020/120281,公开号WO2021068952A1中的权利要求书所记载;
其中,X、Y、Z、R、T、A以及X10的定义如专利申请PCT/US2016/062114,公开号WO2017087428A1(对应中国申请号2016800200132,公开号CN108136214A)中的权利要求书所记载;
其中:
A是取代或未经取代的C6-C10的芳基、联芳基或取代的联芳基、5-15元的杂芳基或-N=CR1R2,其中取代时的取代基选自由以下组成的群:卤基、-CN、-NO2、–O-(CH2)-O-、-CO2H及其盐、-OR100、-CO2R100、-CONR101R102、-NR101R102、-NR100SO2R100、-SO2R100、-SO2NR101R102、C1-C6烷基、C3-C10杂环基;
其中,R100、R101及R102各自独立是氢、C1-C8烷基、C6-C12芳基;或R101及R102与其附接至的氮原子一起形成5-7元杂环;
其中烷基及芳基各自是经1-3个卤基或1-3个C1-C6烷基取代;
R1及R2各自独立是苯基或甲基;
X、Y及Z各自独立是氢或卤基;
R是氢或C1-C6烷基或卤素取代烷基。
3.根据权利要求1-2中任一项所述的治疗方法,其中,KRAS突变选自KRAS-G12D突变、KRAS-G12V和KRAS-G12C突变,优选自KRAS-G12D突变。
4.根据权利要求1-2中任一项所述的治疗方法,其中,其他治疗药物选自KRAS抑制剂、免疫治疗药物,KRAS抑制剂优选自Sotorasib(AMG510)、adagrasib(MRTX849)、GDC6036、LY3499446、JNJ74699157(ARS3248)、D-1553,免疫治疗药物优选自PD-1单抗、PD-L1单抗。
6.AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途。
7.AKR1C3活化的DNA烷化剂前药化合物在制备单药或联用其他治疗药物治疗KRAS突变的癌症、肿瘤患者的中的制药用途,该化合物选自结构式1/2/3/4/5/6及其盐、酯、溶剂合物、同位素异构体:
其中,R1、R2、R3、R4、R5、R8、R9、R10的定义如专利申请PCT/CN2020/089692,公开号WO2020228685A1中的权利要求书所记载;
其中,A、E、G、X、Y的定义如专利申请PCT/NZ2019/050030,公开号WO2019190331A1(对应中国申请号2019800234236,公开号CN111918864A)中的权利要求书所记载;
其中,Rw的定义如专利申请PCT/CN2020/120281,公开号WO2021068952A1中的权利要求书所记载;
其中,X、Y、Z、R、T、A以及X10的定义如专利申请PCT/US2016/062114,公开号WO2017087428A1(对应中国申请号2016800200132,公开号CN108136214A)中的权利要求书所记载;
其中:
A是取代或未经取代的C6-C10的芳基、联芳基或取代的联芳基、5-15元的杂芳基或-N=CR1R2,其中取代时的取代基选自由以下组成的群:卤基、-CN、-NO2、–O-(CH2)-O-、-CO2H及其盐、-OR100、-CO2R100、-CONR101R102、-NR101R102、-NR100SO2R100、-SO2R100、-SO2NR101R102、C1-C6烷基、C3-C10杂环基;
其中,R100、R101及R102各自独立是氢、C1-C8烷基、C6-C12芳基;或R101及R102与其附接至的氮原子一起形成5-7元杂环;
其中烷基及芳基各自是经1-3个卤基或1-3个C1-C6烷基取代;
R1及R2各自独立是苯基或甲基;
X、Y及Z各自独立是氢或卤基;
R是氢或C1-C6烷基或卤素取代烷基。
8.根据权利要求6或7所述的制药用途,其中,KRAS突变选自KRAS-G12D突变、KRAS-G12V和KRAS-G12C突变,优选自KRAS-G12D突变。
9.根据权利要求6或7所述的制药用途,其中,其他治疗药物选自KRAS抑制剂、免疫治疗药物,KRAS抑制剂优选自Sotorasib(AMG510)、adagrasib(MRTX849)、GDC6036、LY3499446、JNJ74699157(ARS3248)、D-1553,免疫治疗药物优选自PD-1单抗、PD-L1单抗。
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Application publication date: 20230331 |