Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer
Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer
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针对结直肠癌中 Hsp90-Cdc37 蛋白-蛋白相互作用的小分子抑制剂
DOI：
10.1126/sciadv.aax2277
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发表时间：
2019-09-01
期刊：
影响因子：
13.6
通讯作者：
You, Qidong
中科院分区：
文献类型：
--
作者：
Wang, Lei;Zhang, Lixiao;You, Qidong
直接破坏Hsp90-Cdc37复合物可以选择性下调Hsp90的激酶客户并实现细胞周期停滞。破坏 Hsp90 和 Cdc37 之间的相互作用正在成为一种以不涉及三磷酸腺苷抑制的方式调节 Hsp90 分子伴侣循环的替代且特定的方法。在此，我们将 DDO-5936 鉴定为结直肠癌中 Hsp90-Cdc37 蛋白-蛋白相互作用 (PPI) 的小分子抑制剂。 DDO-5936 通过与 Hsp90 上先前未知的位点（涉及 Glu47）（Hsp90-Cdc37 PPI 的结合决定簇之一）结合，在体外和体内破坏 Hsp90-Cdc37 PPI，从而导致 HCT116 细胞中 Hsp90 激酶客户的选择性下调。此外，DDO-5936 对 Hsp90-Cdc37 复合物形成的抑制导致细胞周期蛋白依赖性激酶 4 显着减少，并随后通过 Cdc37 依赖性细胞周期停滞抑制细胞增殖。总之，我们的结果证明 DDO-5936 是一种已确定的 Hsp90-Cdc37 PPI 特异性小分子抑制剂，可用于全面研究针对癌症治疗的 Hsp90 分子伴侣周期的替代方法。
Directly disrupting the Hsp90-Cdc37 complex can selectively down-regulate kinase clients of Hsp90 and achieve cell cycle arrest. Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu47, one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.