RT Journal Article SR Electronic T1 Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaax2277 DO 10.1126/sciadv.aax2277 VO 5 IS 9 A1 Wang, Lei A1 Zhang, Lixiao A1 Li, Li A1 Jiang, Jingsheng A1 Zheng, Zhen A1 Shang, Jialin A1 Wang, Chengxiang A1 Chen, Weilin A1 Bao, Qichao A1 Xu, Xiaoli A1 Jiang, Zhengyu A1 Zhang, Jian A1 You, Qidong YR 2019 UL http://advances.sciencemag.org/content/5/9/eaax2277.abstract 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.