title: ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system.
abstract: 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.
authors.affiliation: Medical Research Council Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK. sigrun.polier@sussex.ac.uk
authors.forename: Sigrun
authors.initials: S
authors.lastname: Polier
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Samant
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018833:Chaperonins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013449:Sulfonamides; D000077341:Lapatinib; D000077484:Vemurafenib; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D018833:Chaperonins