公开(公告)号：WO2017087810A1

公开(公告)日：2017-05-26

申请号：PCT/US2016/062789

申请日：2016-11-18

Applicant: MEMORIAL SLOAN-KETTERING CANCER CENTER

Inventor： CHENG, Emily, H. ,  HSIEH, James

IPC: G01N33/50 ,  G01N33/574

CPC classification number: G01N33/5011 ,  A61K31/00 ,  G01N2510/00

Abstract: A method of identifying inhibitors of the anti-apoptotic survival pathway in cancer cells is disclosed. The method comprises the steps of (a) exposing cultured wild-type cells to a candidate inhibitor at a predetermined concentration for a predetermined period of time and determining cell viability after the exposure to the candidate inhibitor; (b) exposing two or more cell lines of specifically MCL-1 or BCL-2 or BCL-X L addicted cells to the candidate inhibitor at the predetermined concentration for the predetermined period of time and determining cell viability after the exposure to the candidate inhibitor; and (c) identifying the candidate inhibitor as a MCL-1 or BCL-2 or BCL-X L inhibitor if the cell viability in step (a) is significantly higher than the cell viability in step (b). The disclosed method provides a way to identify inhibitors which selectively inhibit specific members of the BCL-2 family ( e.g ., MCL-1) by screening two or more cell lines with addictions to different and specific members of the BCL-2 family of proteins.

Abstract translation: 公开了一种鉴定癌细胞中抗凋亡存活途径抑制剂的方法。 该方法包括以下步骤：（a）将培养的野生型细胞暴露于预定浓度的候选抑制剂达预定时间段，并测定暴露于候选抑制剂后的细胞活力; （b）将特定MCL-1或BCL-2或BCL-XL嗜中性细胞的两种或更多种细胞系暴露于预定浓度的候选抑制剂达预定时间段并测定细胞活力 暴露于候选抑制剂后; 和（c）如果步骤（a）中的细胞活力显着高于步骤（b）中的细胞活力，则鉴定候选抑制剂为MCL-1或BCL-2或BCL-XL抑制剂 ）。 所公开的方法提供了一种通过筛选两种或更多种细胞系选择性抑制BCL-2家族的特定成员（例如，MCL-1）的抑制剂的方法，所述细胞系对不同的和特定成员 BCL-2家族蛋白质。

公开(公告)号：WO2017027841A1

公开(公告)日：2017-02-16

申请号：PCT/US2016/046889

申请日：2016-08-12

Applicant: MEMORIAL SLOAN-KETTERING CANCER CENTER ,  CHENG, Emily, H. ,  HSIEH, James

Inventor： CHENG, Emily, H. ,  HSIEH, James ,  JENG, Paul ,  OUERFELLI, Ouathek ,  YANG, Guangli

IPC: C07D307/82 ,  A61K31/343 ,  A61P35/00 ,  A61P19/02 ,  A61P37/00

CPC classification number: C07D307/82 ,  A61K31/343

Abstract: Described herein are phenylsulfonamido-benzofuran derivatives, and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions, methods, uses, and kits involving compounds of Formulae (I), (II), (III), (IV), (V), or (VI) for treating and/or preventing proliferative diseases (e.g. cancers, inflammatory diseases, and autoimmune diseases) in a subject. The compounds and pharmaceutical compositions as described herein inhibit at least one protein of the BCL-2 family in a biological sample or subject to treat and/or prevent a proliferative disease. In certain embodiments, compounds described herein are selective inhibitors of MCL-1, a BCL-2 family member protein.

Abstract translation: 本文描述了苯基磺酰氨基苯并呋喃衍生物及其药学上可接受的盐。 还提供了涉及用于治疗和/或预防增殖性疾病（例如，增殖性疾病）的式（I），（II），（III）， 癌症，炎性疾病和自身免疫性疾病）。 如本文所述的化合物和药物组合物在生物样品或受试者中抑制BCL-2家族的至少一种蛋白质以治疗和/或预防增殖性疾病。 在某些实施方案中，本文描述的化合物是MCL-1（BCL-2家族成员蛋白质）的选择性抑制剂。

公开(公告)号：WO2017027845A1

公开(公告)日：2017-02-16

申请号：PCT/US2016/046897

申请日：2016-08-12

Applicant: MEMORIAL SLOAN-KETTERING CANCER CENTER ,  ALBERT EINSTEIN COLLEGE OF MEDICINE, INC. ,  CHENG, Emily, H. ,  HSIEH, James ,  GAVATHIOTIS, Evripidis

Inventor： CHENG, Emily, H. ,  HSIEH, James ,  GAVATHIOTIS, Evripidis ,  JENG, Paul ,  OUERFELLI, Ouathek ,  YANG, Guangli

IPC: A61K31/343 ,  A61P35/00 ,  A61P19/02 ,  A61P37/00 ,  C07D307/82

CPC classification number: C07D307/82 ,  A61K31/343

Abstract: Described herein are phenylsulfonamido-benzofuran derivatives, and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions, methods, uses, and kits involving compounds of Formulae (I), (II), (III), (IV), (V), or (VI) for treating and/or preventing proliferative diseases (e.g. cancers, inflammatory diseases, and autoimmune diseases) in a subject. The compounds and pharmaceutical compositions as described herein inhibit at least one protein of the BCL-2 family in a biological sample or subject to treat and/or prevent a proliferative disease. In certain embodiments, compounds described herein are selective inhibitors of MCL-1, a BCL-2 family member protein.

Abstract translation: 本文描述的是苯基磺酰氨基 - 苯并呋喃衍生物及其药学上可接受的盐。 还提供了用于治疗和/或预防增殖性疾病的药物组合物，方法，用途和试剂盒，其包括式（I），（II），（III），（IV），（V）或（VI） 癌症，炎性疾病和自身免疫性疾病）。 本文所述的化合物和药物组合物抑制生物样品或受试者中BCL-2家族的至少一种蛋白质以治疗和/或预防增殖性疾病。 在某些实施方案中，本文所述的化合物是MCL-1（BCL-2家族成员蛋白）的选择性抑制剂。