A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival.
A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival.
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DOI：
10.1016/j.chembiol.2012.07.018
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发表时间：
2012-09-21
影响因子：
--
通讯作者：
Walensky LD
中科院分区：
文献类型：
--
作者：
Cohen NA;Stewart ML;Gavathiotis E;Tepper JL;Bruekner SR;Koss B;Opferman JT;Walensky LD
癌细胞劫持bcl2家族生存蛋白以抑制死亡效应，从而实现永生状态。这是通过中和死亡蛋白的促凋亡的BH3α-螺旋的抗凋亡表面沟槽来实现的。尤其是抗凋亡的MCL-1已经成为癌症中普遍存在的耐药因子。虽然靶向bcl2抗凋亡亚类可以有效地恢复bcl2依赖癌症的死亡途径，但针对mcl1结合特异性的分子开发一直滞后。我们先前发现，碳氢化合物钉扎的MCL-1BH3螺旋是一种选择性很好的MCL-1拮抗剂。通过在竞争性筛选中部署这种独特的试剂，我们鉴定了一种MCL-1抑制分子，它选择性地靶向MCL-1的BH3结合槽，中和其对细胞凋亡的生化锁定，并在MCL-1依赖的特定背景下诱导caspase激活和白血病细胞死亡。
Cancer cells hijack BCL-2 family survival proteins to suppress the death effectors and thereby enforce an immortal state. This is accomplished biochemically by an anti-apoptotic surface groove that neutralizes the pro-apoptotic BH3 α-helix of death proteins. Anti-apoptotic MCL-1 in particular has emerged as a ubiquitous resistance factor in cancer. Whereas targeting the BCL-2 anti-apoptotic subclass effectively restores the death pathway in BCL-2-dependent cancer, the development of molecules tailored to the binding specificity of MCL-1 has lagged. We previously discovered that a hydrocarbon-stapled MCL-1 BH3 helix is an exquisitely selective MCL-1 antagonist. By deploying this unique reagent in a competitive screen, we identified an MCL-1 inhibitor molecule that selectively targets the BH3-binding groove of MCL-1, neutralizes its biochemical lockhold on apoptosis, and induces caspase activation and leukemia cell death in the specific context of MCL-1 dependence.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
7.3
作者：
Feng, Yu;Ding, Xiao;Liu, Dongxiang
通讯作者：
Liu, Dongxiang
影响因子：
64.8
作者：
Gavathiotis, Evripidis;Suzuki, Motoshi;Davis, Marguerite L.;Pitter, Kenneth;Bird, Gregory H.;Katz, Samuel G.;Tu, Ho-Chou;Kim, Hyungjin;Cheng, Emily H. -Y.;Tjandra, Nico;Walensky, Loren D.
通讯作者：
Walensky, Loren D.
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A