Correction to Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold.
Correction to Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold.
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基于新支架对具有亚纳摩尔结合亲和力的 Bcl-2 和 Bcl-xL 抑制剂的设计进行修正。
DOI：
10.1021/jm300728g
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发表时间：
2012
影响因子：
7.3
通讯作者：
Wang,Shaomeng
中科院分区：
文献类型：
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作者：
Zhou,Haibin;Chen,Jianfang;Meagher,JenniferL;Yang,Chao-Yie;Aguilar,Angelo;Liu,Liu;Bai,Longchuan;Cong,Xin;Cai,Qian;Fang,Xueliang;Stuckey,JeanneA;Wang,Shaomeng
采用基于结构的策略，我们设计了一类新的有效的抗凋亡蛋白Bcl-2和Bcl-xL的小分子抑制剂。基于Bcl-xL的晶体结构和美国食品和药物管理局（FDA）批准的药物设计了具有新支架的初始先导化合物，发现其对Bcl-2和Bcl-xL的亲和力均为100 μM。将该弱先导物连接到另一个衍生自Abbott的ABT-737的弱亲和力片段导致结合亲和力提高>10 000倍。进一步优化最终产生了对Bcl-2和Bcl-xL具有亚纳摩尔结合亲和力和有效细胞活性的化合物。最佳化合物（21）以Ki < 1 nM结合Bcl-xL和Bcl-2，以60-90 nM的IC 50值抑制H146和H1417小细胞肺癌细胞系中的细胞生长，并在30-100 nM下诱导H146癌细胞系中的稳健细胞死亡。
Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 μM for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott’s ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 withKi< 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC50values of 60–90 nM, and induces robust cell death in the H146 cancer cell line at 30–100 nM.