Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors
Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors
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作为选择性 Mcl-1 抑制剂的 1-取代-吲哚-2-羧酸的基于片段的设计、合成和生物学评价
DOI：
10.1002/ardp.201600251
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发表时间：
2017
影响因子：
5.1
通讯作者：
Zhang Zhichao
中科院分区：
文献类型：
--
作者：
Wang Ziqian;Xu Wenjie;Song Ting;Guo Zongwei;Liu Lu;Fan Yudan;Wang Anhui;Zhang Zhichao
基于已知的选择性Mcl-1抑制剂6-氯-3-（3-（4-氯-3，5-二甲基苯氧基）丙基）-1H-吲哚-2-羧酸，我们应用基于片段的方法获得了延伸到BH 3沟的p1口袋中的新分子，然后表现出对Mcl-1的结合选择性超过Bcl-2蛋白。在我们从母体分子中解构1H-吲哚-2-羧酸后，在1-位取代苯磺酰基，以根据X射线晶体学鉴定的母体分子的结合模式采用优选的几何结构进入p1口袋。配体结合自由能（ΔG）与非氢重原子数（HAC）之间存在线性关系。最后，我们不仅获得了化合物12对Mcl-1（Ki= 0.48 µM，通过荧光偏振）的选择性是Bcl-2（Ki= 3.6 µM）的7.5倍，而且还提供了证据表明，p1口袋的额外占据比Bcl-2结合更有利于Mcl-1，并且比占据p2口袋对Mcl-1抑制的贡献更大。化合物12对Mcl-1依赖性癌细胞表现出选择性杀伤能力。
Based on a known selective Mcl‐1 inhibitor, 6‐chloro‐3‐(3‐(4‐chloro‐3,5‐dimethylphenoxy)propyl)‐1H‐indole‐2‐carboxylic acid, we applied a fragment‐based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl‐1 over the Bcl‐2 protein. After we deconstructed the 1H‐indole‐2‐carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1‐position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X‐ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non‐hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound12with a 7.5‐fold selectivity to Mcl‐1 (Ki= 0.48 µM by fluorescence polarization) over Bcl‐2 (Ki= 3.6 µM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl‐1 than for Bcl‐2 binding, and contributes more to Mcl‐1 inhibition than occupation of the p2 pocket. Compound12exhibited a selective killing ability on Mcl‐1‐dependent cancer cells.