期刊
ISCIENCE
卷 25, 期 10, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2022.105064
关键词
-
资金
- ALSAC
- National Institutes of Health [R37CA248565, R01DK125263]
- Alex's Lemonade Stand Foundation for Childhood Cancers
- Blavatnik Institute at Harvard
The small molecule SJ572946 selectively activates BAK over BAX, showing cytotoxic effects on cancer cells, and can be used in combination with other apoptotic inducers and BH3 mimetics.
Poration of the outer mitochondrial membrane by the effector BCL-2 proteins BAK and BAX initiates apoptosis. BH3-only initiators BID and BIM trigger conformational changes in BAK and BAX transforming themfromglobular dormant proteins to oligomers of the apoptotic pores. Small molecules that can directly activate effectors are being sought for applications in cancer treatment. Here, we describe the small molecule SJ572946, discovered in a fragment-based screen that binds to the activation groove of BAK and selectively triggers BAK activation over that of BAX in liposome and mitochondrial permeabilization assays. SJ572946 independently kills BAK-expressing BCL2allKO HCT116 cells revealing on target cellular activity. In combination with apoptotic inducers and BH3 mimetics, SJ572946 kills experimental cancer cell lines. SJ572946 also cooperates with the endogenous BAK activator BID in activating a misfolded BAK mutant substantially impaired in activation. SJ572946 is a proof- of-concept tool for probing BAK-mediated apoptosis in preclinical cancer research.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据