Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2.

Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE

Original Publication: New York, NY : Nature Pub. Group, [2005]-

HSP90 Heat-Shock Proteins/*antagonists & inhibitors ; Neoplasms/*metabolism ; Purines/*pharmacology ; Receptor, ErbB-2/*metabolism; HSP90 Heat-Shock Proteins/chemistry ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Neoplasms/pathology ; Purines/chemical synthesis ; Purines/chemistry ; Structure-Activity Relationship

Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90β, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.

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R21 AI090501 United States AI NIAID NIH HHS; R01 CA172546-01A1 United States CA NCI NIH HHS; UL1 RR024996 United States RR NCRR NIH HHS; R01 CA155226 United States CA NCI NIH HHS; R21 CA158609 United States CA NCI NIH HHS; U01 AG032969-01A1 United States AG NIA NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R01 CA155226-01 United States CA NCI NIH HHS; R01 CA172546 United States CA NCI NIH HHS; R21 CA158609-01 United States CA NCI NIH HHS; R01 CA095130 United States CA NCI NIH HHS; R03 NS050838 United States NS NINDS NIH HHS; R03 MH076408 United States MH NIMH NIH HHS; U01 AG032969 United States AG NIA NIH HHS

PDB 3O0I; 3O2F
PubChem-Substance 163826355; 163826356; 163826357; 163826358; 163826359; 163826360; 163826361; 163826362; 163826363; 163826364; 163826365; 163826366; 163826367; 163826368; 163826369; 163826370; 163826371; 163826372; 163826373; 163826374; 163826375; 163826376

0 (HSP90 Heat-Shock Proteins)
0 (Purines)
EC 2.7.10.1 (ERBB2 protein, human)
EC 2.7.10.1 (Receptor, ErbB-2)
W60KTZ3IZY (purine)

Date Created: 20130903 Date Completed: 20140109 Latest Revision: 20220409

20231215

PMC3982621

10.1038/nchembio.1335

23995768