公开(公告)号：WO2017070256A3

公开(公告)日：2017-05-18

申请号：PCT/US2016057774

申请日：2016-10-19

申请人： ARAXES PHARMA LLC

发明人： PATRICELLI MATTHEW P ,  PETERS ULF ,  LI LIANSHENG ,  REN PINGDA ,  LIU YI

IPC分类号： A61K31/496 ,  A61K31/517 ,  C07D239/74 ,  C07D239/94 ,  C07D239/95 ,  C07D241/04

CPC分类号： G01N33/573 ,  C12N9/14 ,  C12Y306/05002 ,  G01N2500/04 ,  G01N2500/20

摘要： Provided herein are compositions, reactions mixtures, mutant Ras proteins, kits, substrates, and systems for selecting a Ras antagonist, as well as methods of using the same. The present disclosure provides a method of selecting a Ras antagonist. In some embodiments, the method comprises a mutant Ras, wherein the mutant Ras comprises a cysteine mutation; a competition probe, and a test compound;, and detecting binding between the mutant Ras and the competition probe; comparing the binding between the mutant Ras and the competition probe in the absence of the test compound; wherein a decrease in binding between the mutant Ras and the competition probe is indicative of Ras antagonist activity of the test compound. In some embodiments, the cysteine mutation is E62C; E72C; A100C; E73C; D92C; H102C; Q130C; E103C; A103C; E1 10C; H95C; Q95C; L95C; R105C; Q133C; K106C; D106C; E106C; or E1 13C relative to SEQ ' ID NO: 1.

摘要翻译： 本文提供了用于选择Ras拮抗剂的组合物，反应混合物，突变Ras蛋白，试剂盒，底物和系统，以及使用它们的方法。 本公开提供了选择Ras拮抗剂的方法。 在一些实施方案中，所述方法包含突变型Ras，其中所述突变型Ras包含半胱氨酸突变; 竞争探针和测试化合物;以及检测突变Ras和竞争探针之间的结合; 比较不存在测试化合物时突变Ras和竞争探针之间的结合; 其中突变Ras和竞争探针之间结合的减少指示测试化合物的Ras拮抗剂活性。 在一些实施方案中，半胱氨酸突变是E62C; E72C; A100C; E73C; D92C; H102C; Q130C; E103C; A103C; E1 10C; H95C; Q95C; L95C; R105C; Q133C; K106C; D106C; E106C; 或E1 13C相对于SEQ ID NO：1。

公开(公告)号：WO2017070256A8

公开(公告)日：2017-06-08

申请号：PCT/US2016057774

申请日：2016-10-19

申请人： ARAXES PHARMA LLC

发明人： PATRICELLI MATTHEW P ,  PETERS ULF ,  LI LIANSHENG ,  REN PINGDA ,  LIU YI

IPC分类号： A61K31/496 ,  A61K31/517 ,  C07D239/74 ,  C07D239/94 ,  C07D239/95 ,  C07D241/04

CPC分类号： G01N33/573 ,  C12N9/14 ,  C12Y306/05002 ,  G01N2500/04 ,  G01N2500/20

摘要： Provided herein are compositions, reactions mixtures, mutant Ras proteins, kits, substrates, and systems for selecting a Ras antagonist, as well as methods of using the same. The present disclosure provides a method of selecting a Ras antagonist. In some embodiments, the method comprises a mutant Ras, wherein the mutant Ras comprises a cysteine mutation; a competition probe, and a test compound;, and detecting binding between the mutant Ras and the competition probe; comparing the binding between the mutant Ras and the competition probe in the absence of the test compound; wherein a decrease in binding between the mutant Ras and the competition probe is indicative of Ras antagonist activity of the test compound. In some embodiments, the cysteine mutation is E62C; E72C; A100C; E73C; D92C; H102C; Q130C; E103C; A103C; E1 10C; H95C; Q95C; L95C; R105C; Q133C; K106C; D106C; E106C; or E1 13C relative to SEQ ' ID NO: 1.

公开(公告)号：WO2016164675A8

公开(公告)日：2017-05-11

申请号：PCT/US2016026573

申请日：2016-04-08

申请人： ARAXES PHARMA LLC

发明人： LI LIANSHENG ,  FENG JUN ,  LONG YUN OLIVER ,  LIU YUAN ,  WU TAO ,  REN PINGDA ,  LIU YI

IPC分类号： C07D403/12 ,  C07D239/74 ,  C07D239/94 ,  C07D239/95 ,  C07D401/04 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D403/14 ,  C07D405/12 ,  C07D405/14 ,  C07D409/12 ,  C07D413/12 ,  C07D417/04 ,  C07D471/08

CPC分类号： C07D239/74 ,  C07D239/94 ,  C07D239/95 ,  C07D401/04 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D403/12 ,  C07D403/14 ,  C07D405/12 ,  C07D405/14 ,  C07D409/12 ,  C07D413/12 ,  C07D417/04 ,  C07D471/08 ,  C07D487/10 ,  C07D491/10 ,  C07F9/65583

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have one of the following structures (I), (II) or (III): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5a, R5b, R6, A, B, G1, G2, L1, L2, m1, m2, n, x, y, X and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

摘要翻译： 提供了具有作为G12C突变KRAS蛋白抑制剂活性的化合物。 该化合物具有以下结构（I），（II）或（III）之一：或其药学上可接受的盐，立体异构体或前药，其中R1，R2a，R2b，R2c，R3a，R3b，R4a，R4b，R5a， R5b，R6，A，B，G1，G2，L1，L2，m1，m2，n，x，y，X和E如本文所定义。 还提供了与这些化合物的制备和使用有关的方法，包含此类化合物的药物组合物以及调节G12C突变KRAS蛋白质活性以治疗疾病如癌症的方法。