Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker.
Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker.
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DOI：
10.1016/j.bmc.2013.08.017
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发表时间：
2013-11-01
影响因子：
3.5
通讯作者：
Cardone MH
中科院分区：
文献类型：
--
作者：
Richard DJ;Lena R;Bannister T;Blake N;Pierceall WE;Carlson NE;Keller CE;Koenig M;He Y;Minond D;Mishra J;Cameron M;Spicer T;Hodder P;Cardone MH
抗凋亡Bcl-2家族蛋白是重要的肿瘤治疗靶点。迄今为止，消除抗凋亡活性的BH 3模拟物主要针对Bcl-2和/或Bcl-xL。一种观察到的对这些抑制剂的抗性机制是暴露于此类治疗剂的细胞中Mcl-1水平增加。由于这个原因，并且由于Mcl-1在淋巴、骨髓和其他癌症的发病中很重要，因此它已成为人们非常感兴趣的靶点。然而，缺乏对Mcl-1显示效力和选择性的小分子抑制剂。由于难以将在生物化学水平上观察到的靶标选择性转化为细胞水平，因此鉴定此类化合物具有挑战性。在这里，我们报告的HTS策略加上定向命中优化的结果。鉴定的化合物具有选择性Mcl-1抑制活性，对Bcl-xL的亲和力降低超过100倍。这些化合物在细胞水平上的选择性使用BH 3分析（一种新的个性化诊断方法）进行了验证。该测定提供了一种重要的功能性生物标志物，其允许基于细胞对各种抗凋亡Bcl-2蛋白的依赖性来表征细胞。我们证明，依赖于Mcl-1或Bcl-2/Bcl-xL生存的细胞对真正靶向这些蛋白质的化合物有明显的反应。化合物9的鉴定具有独特的验证和选择性Mcl-1抑制活性，为研究内在细胞凋亡途径的人提供了一个有价值的工具，并突出了开发一流癌症治疗剂的重要方法。
Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
9
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：
2.9
作者：
Acoca, Stephane;Cui, Qizhi;Purisima, Enrico O.
通讯作者：
Purisima, Enrico O.
影响因子：
11.5
作者：
Hussain, Syed-Rehan A.;Cheney, Carolyn M.;Byrd, John C.
通讯作者：
Byrd, John C.