Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B
Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B
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同时靶向磷酸酶 Cdc25B 活性位点和热点的三嗪二价药物的设计、合成和功能评估
DOI：
10.1016/j.bmcl.2021.128265
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ohkanda Junko
中科院分区：
文献类型：
--
作者：
Nagaoka Yosei;Parvatkar Prakash;Hirai Go;Ohkanda Junko
Cdc25B磷酸酶催化细胞周期蛋白依赖性激酶2 （CDK2/CycA）的去磷酸化和激活，并且它们在癌症中的过表达已被报道。尽管Cdc25B作为一种药物靶点受到了广泛的关注，但其平坦且无特征的表面使得开发针对该蛋白的新药物具有挑战性。在这项研究中，我们研究了一系列基于二价三嗪的衍生物的合理设计，目的是同时靶向与CDK2/CycA相互作用的活性位点和远程热点。含有芳香残基的化合物1和10在低微摩尔浓度下选择性地抑制Cdc25B活性。
Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds1eand10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration.