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.