Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer

Lei Wang, Lixiao Zhang, Li Li, Jingsheng Jiang, Zhen Zheng, Jialin Shang, Chengxiang Wang, Weilin Chen, Qichao Bao, Xiaoli Xu, Zhengyu Jiang, Jian Zhang, Qidong You

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaax2277
JournalScience Advances
Volume5
Issue number9
DOIs
StatePublished - Sep 18 2019
Externally publishedYes

ASJC Scopus subject areas

  • General

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