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ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system
journal contribution
posted on 2023-06-08, 14:38 authored by Sigrun Polier, Rahul S Samant, Paul A Clarke, Paul Workman, Chrisostomos ProdromouChrisostomos Prodromou, Laurence PearlLaurence PearlProtein 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.
History
Publication status
- Published
Journal
Nature Chemical BiologyISSN
1552-4450Publisher
Nature Publishing GroupExternal DOI
Issue
5Volume
9Page range
307-312Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2013-03-26Usage metrics
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