Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer
Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer
复制标题
发现并优化针对热休克蛋白 90 (Hsp90) 和细胞分裂周期 37 的蛋白质与蛋白质相互作用的小分子，作为治疗结直肠癌的口服活性抑制剂
DOI：
10.1021/acs.jmedchem.9b01659
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发表时间：
2020-02-13
影响因子：
7.3
通讯作者：
You, Qidong
中科院分区：
文献类型：
--
作者：
Wang, Lei;Jiang, Jingsheng;You, Qidong
细胞分裂周期37(CDC37)是一种蛋白特异性辅伴蛋白，通过与热休克蛋白90的蛋白-蛋白相互作用(PPI)选择性地调节蛋白激酶的成熟。直接干扰Hsp90-CDC37 PPI是一种通过Hsp90的激酶客户的特定抑制方式来开发抗癌药物的替代策略。基于本课题组首次报道的针对Hsp90-CDC37 PPI的特异性小分子抑制剂(DDO-S936)，我们进行了初步的构效关系和药效学评价，以提高其效力和类药物特性。在这里，我们的努力得到了目前最好的抑制剂18h，具有更好的结合亲和力(K-d=0.5µM)和细胞抑制活性(IC50=1.73µM)。体外和体内实验表明，18h可以有效地阻断Hsp90-CDc37的相互作用，从而特异性地抑制Hsp90的激酶客户。此外，18h具有理想的理化性质和良好的稳定性，在体内具有口服效果。
Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-S936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (K-d = 0.5 mu M) and cellular inhibitory activity (IC50 = 1.73 mu M). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.