Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity

被引：128

作者：

Bruncko, Milan ^{[1
]}

Wang, Le ^{[1
]}

Sheppard, George S. ^{[1
]}

Phillips, Darren C. ^{[1
]}

Tahir, Stephen K. ^{[1
]}

Xue, John ^{[1
]}

Erickson, Scott ^{[1
]}

Fidanze, Steve ^{[1
]}

Fry, Elizabeth ^{[1
]}

Hasvold, Lisa ^{[1
]}

Jenkins, Gary J. ^{[1
]}

Jin, Sha ^{[1
]}

Judge, Russell A. ^{[1
]}

Kovar, Peter J. ^{[1
]}

Madar, David ^{[1
]}

Nimmer, Paul ^{[1
]}

Park, Chang ^{[1
]}

Petros, Andrew M. ^{[1
]}

Rosenberg, Saul H. ^{[1
]}

Smith, Morey L. ^{[1
]}

Song, Xiaohong ^{[1
]}

Sun, Chaohong ^{[1
]}

Tao, Zhi-Fu ^{[1
]}

Wang, Xilu ^{[1
]}

Xiao, Yu ^{[1
]}

Zhang, Haichao ^{[1
]}

Tse, Chris ^{[1
]}

Leverson, Joel D. ^{[1
]}

Elmore, Steven W. ^{[1
]}

Souers, Andrew J. ^{[1
]}

机构：

[1] AbbVie Inc, N Chicago, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 05期

关键词：

ANTI-APOPTOTIC MCL-1; SMALL-MOLECULE INHIBITOR; IN-VIVO; TARGETING MCL-1; CELL-LINES; DISCOVERY; CANCER; POTENT; FAMILY; SURVIVAL;

D O I：

10.1021/jm501258m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.

引用

页码：2180 / 2194

页数：15

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