title: Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2.
abstract: 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.
authors.affiliation: 1] Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York, USA. [2] Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA. [3].
authors.forename: Pallav D
authors.initials: PD
authors.lastname: Patel
authors.forename: Pengrong
authors.initials: P
authors.lastname: Yan
authors.forename: Paul M
authors.initials: PM
authors.lastname: Seidler
authors.forename: Hardik J
authors.initials: HJ
authors.lastname: Patel
authors.forename: Weilin
authors.initials: W
authors.lastname: Sun
authors.forename: Chenghua
authors.initials: C
authors.lastname: Yang
authors.forename: Nanette S
authors.initials: NS
authors.lastname: Que
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.forename: Paola
authors.initials: P
authors.lastname: Finotti
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Stephani
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Gewirth
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
mesh_terms: D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C030985:purine