Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries
Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries
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从基于小型化点击化学的组合库中鉴定高效且选择性的 Cdc25 蛋白磷酸酶抑制剂
DOI：
10.1016/j.ejmech.2019.111696
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发表时间：
2019-12-01
影响因子：
6.7
通讯作者：
Zhan, Peng
中科院分区：
文献类型：
--
作者：
Jing, Lanlan;Wu, Gaochan;Zhan, Peng
细胞分裂周期25（Cdc 25）蛋白磷酸酶在细胞周期阶段之间的转换中起关键作用，并且它们与各种癌症的关联已被广泛证明，这使得它们成为抗癌治疗的理想靶标。尽管已经开发了几种Cdc 25抑制剂，但大多数都表现出低活性和较差的亚型选择性。因此，寻找对Cdc 25亚型具有高效活性和显著选择性的新型小分子抑制剂，不仅可以作为治疗癌症的药物，而且可以探索其转化机制，具有十分重要的意义。在这项研究中，微型化的平行点击化学合成通过CuAAC反应，然后在原位生物筛选被用来发现选择性Cdc 25抑制剂。生物测定结果表明，化合物M2 N12被证明是最有效的Cdc 25抑制剂，其也作为高选择性Cdc 25 C抑制剂，并且是NSC 663284的约9倍效力。此外，M2 N12对KB-VIN细胞系显示出显著的抗生长活性，与PXL和NSC 663284相当。进一步采用全原子分子动力学（MD）模拟方法来探测M2 N12相对于其结构同系物Cdc 25 A和Cdc 25 B对Cdc 25 C的显著选择性。总之，上述结果使M2 N12成为一个有前途的先导化合物，用于进一步研究和结构修饰。(C)2019 Elsevier Masson SAS。All rights reserved.
Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification. (C) 2019 Elsevier Masson SAS. All rights reserved.