Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

被引：368

作者：

Leverson, J. D. ^{[1
]}

Zhang, H. ^{[1
]}

Chen, J. ^{[1
]}

Tahir, S. K. ^{[1
]}

Phillips, D. C. ^{[1
]}

Xue, J. ^{[1
]}

Nimmer, P. ^{[1
]}

Jin, S. ^{[1
]}

Smith, M. ^{[1
]}

Xiao, Y. ^{[1
]}

Kovar, P. ^{[1
]}

Tanaka, A. ^{[1
]}

Bruncko, M. ^{[1
]}

Sheppard, G. S.

Wang, L.

Gierke, S. ^{[2
]}

Kategaya, L. ^{[2
]}

Anderson, D. J. ^{[2
]}

Wong, C. ^{[2
]}

Eastham-Anderson, J. ^{[2
]}

Ludlam, M. J. C. ^{[2
]}

Sampath, D. ^{[2
]}

Fairbrother, W. J. ^{[2
]}

Wertz, I. ^{[2
]}

Rosenberg, S. H. ^{[1
]}

Tse, C. ^{[1
]}

Elmore, S. W. ^{[1
]}

Souers, A. J. ^{[1
]}

机构：

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

[2] Genentech Inc, San Francisco, CA 94080 USA

来源：

CELL DEATH & DISEASE | 2015年 / 6卷

关键词：

ANTI-APOPTOTIC MCL-1; BCL-X-L; EFFICIENTLY INDUCES APOPTOSIS; MULTIPLE-MYELOMA CELLS; BH3 MIMETIC ABT-737; IN-VIVO; DOWN-REGULATION; ANTITUMOR-ACTIVITY; FAMILY INHIBITOR; RATIONAL DESIGN;

D O I：

10.1038/cddis.2014.561

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-X-L inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.

引用

页码：e1590 / e1590

页数：11

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