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.