PT - JOURNAL ARTICLE AU - Wang, Lei AU - Zhang, Lixiao AU - Li, Li AU - Jiang, Jingsheng AU - Zheng, Zhen AU - Shang, Jialin AU - Wang, Chengxiang AU - Chen, Weilin AU - Bao, Qichao AU - Xu, Xiaoli AU - Jiang, Zhengyu AU - Zhang, Jian AU - You, Qidong TI - Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer AID - 10.1126/sciadv.aax2277 DP - 2019 Sep 01 TA - Science Advances PG - eaax2277 VI - 5 IP - 9 4099 - http://advances.sciencemag.org/content/5/9/eaax2277.short 4100 - http://advances.sciencemag.org/content/5/9/eaax2277.full SO - Sci Adv2019 Sep 01; 5 AB - 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.