1. Academic Validation
  2. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2

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

  • Nat Chem Biol. 2013 Nov;9(11):677-84. doi: 10.1038/nchembio.1335.
Pallav D Patel 1 Pengrong Yan Paul M Seidler Hardik J Patel Weilin Sun Chenghua Yang Nanette S Que Tony Taldone Paola Finotti Ralph A Stephani Daniel T Gewirth Gabriela Chiosis
Affiliations

Affiliation

  • 1 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].
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18680
    99.94%, HSP Inhibitor
    HSP
  • HY-117395
    99.04%, Grp94 Inhibitor
    HSP