@article{99a54afd8ebb4bf69b1e2053bd9177c8,
title = "Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer",
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.",
author = "Lei Wang and Lixiao Zhang and Li Li and Jingsheng Jiang and Zhen Zheng and Jialin Shang and Chengxiang Wang and Weilin Chen and Qichao Bao and Xiaoli Xu and Zhengyu Jiang and Jian Zhang and Qidong You",
note = "Funding Information: We thank W. Fu and T. Hou (College of Pharmacy, Zhejiang University) for helping with the computational calculations and virtual screening, L. Feng (High-Field NMR Center, College of Chemistry and Chemical Engineering, Xiamen University) and F. Lian (Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences) for NMR assays, and Z. Qiu (School of Traditional Chinese Pharmacy, China Pharmaceutical University) for PK/PD assays. This study was supported by projects 81573346, 81773639, 81773581, and 81602948 of the National Natural Science Foundation of China; BK20160746 and BK20190559 of the Natural Science Foundation of Jiangsu Province of China; CPU2018GY02 of the Double First Class Innovation Team of China Pharmaceutical University; the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program,” China (nos. 2018ZX09711002, 2017ZX09302003, and 2015ZX09101032); the Open Project of State Key Laboratory of Natural Medicines (SKLNMZZCX201803); the China Postdoctoral Science Foundation (no. 2018 M642376); the Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education; and the Young Elite Scientists Sponsorship Program by CAST. Innovation Program of Shanghai Municipal Education Commission (Innovation Program of Shanghai Municipal Education Commission). Publisher Copyright: Copyright {\textcopyright} 2019 The Authors,",
year = "2019",
month = sep,
day = "18",
doi = "10.1126/sciadv.aax2277",
language = "English (US)",
volume = "5",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "9",
}