ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system

Polier, Sigrun, Samant, Rahul S, Clarke, Paul A, Workman, Paul, Prodromou, Chrisostomos and Pearl, Laurence H (2013) ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nature Chemical Biology, 9 (5). pp. 307-312. ISSN 1552-4450

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Protein kinase clients are recruited to the Hsp90 molecular chaperone system via Cdc37, which simultaneously binds Hsp90 and kinases and regulates the Hsp90 chaperone cycle. Pharmacological inhibition of Hsp90 in vivo results in degradation of kinase clients, with a therapeutic effect in dependent tumors. We show here that Cdc37 directly antagonizes ATP binding to client kinases, suggesting a role for the Hsp90-Cdc37 complex in controlling kinase activity. Unexpectedly, we find that Cdc37 binding to protein kinases is itself antagonized by ATP-competitive kinase inhibitors, including vemurafenib and lapatinib. In cancer cells, these inhibitors deprive oncogenic kinases such as B-Raf and ErbB2 of access to the Hsp90-Cdc37 complex, leading to their degradation. Our results suggest that at least part of the efficacy of ATP-competitive inhibitors of Hsp90-dependent kinases in tumor cells may be due to targeted chaperone deprivation.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 26 Mar 2013 09:41
Last Modified: 26 Jun 2013 10:10
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