The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.
The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.
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DOI：
10.1038/nchembio.391
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发表时间：
2010-08
影响因子：
14.8
通讯作者：
Walensky LD
中科院分区：
文献类型：
--
作者：
Stewart ML;Fire E;Keating AE;Walensky LD
开发与病理细胞存活有关的离散抗凋亡BCL-2家族蛋白的选择性抑制剂仍然是一个艰巨而紧迫的挑战。精确定制的化合物将作为分子探针和靶向治疗，以研究和治疗由特异性抗凋亡阻断驱动的人类疾病。特别是，MCL-1已成为人类癌症的主要耐药因子。通过筛选BCL-2结构域（SAHB）的稳定化α-HlS的文库，我们确定MCL-1 BH 3螺旋本身是有效的和排他性的MCL-1抑制剂。X射线晶体学和诱变研究定义了关键的结合和特异性决定因素，包括利用碳氢化合物主食优化亲和力，同时保持选择性的能力。MCL-1 SAHB直接靶向MCL-1，中和其与促凋亡巴克的抑制性相互作用，并使癌细胞对胱天蛋白酶依赖性凋亡敏感。通过利用自然界的配体选择性解决方案，我们产生了一种MCL-1特异性试剂，其定义了靶向MCL-1抑制的结构和功能特征。
The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of Stabilized Alpha-Helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK, and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature’s solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.6
作者：
Day, Catherine L.;Smits, Callum;Hinds, Mark G.
通讯作者：
Hinds, Mark G.
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
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.