Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer
Open Access
- 6 September 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 5 (9), eaax2277
- https://doi.org/10.1126/sciadv.aax2277
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.Funding Information
- National Natural Science Foundation of China (81573346)
- National Natural Science Foundation of China (81773639)
- National Natural Science Foundation of China (81773581)
- National Natural Science Foundation of China (81602948)
- China Postdoctoral Science Foundation (2018M642376)
- Double First Class Innovation Team of China Pharmaceutical University (CPU2018GY02)
- Natural Science Foundation of Jiangsu Province of China (BK2016746)
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