Development of purine-scaffold small molecule inhibitors of Hsp90 Article Report uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Neoplasms

abstract

  • The Hsp90 chaperones play a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype in tumor cells. Agents that interfere with the function of the chaperone may thus be beneficial in the treatment of cancers. The ansamycins (geldanamycin and herbimycin) and the unrelated natural product radicicol were found to bind to the N-terminal pocket of Hsp90 and inhibit its function. However, translation of these compounds to the clinic was impeded by stability and hepatoxicity issues. 17AAG, a derivative of geldanamycin, was found to be less hepatotoxic and is currently undergoing Phase I clinical trial. Unfortunately, 17AAG is insoluble, difficult to formulate and it is not yet clear if therapeutically effective doses can be administered without escalating non-Hsp90 associated toxicities. Additionally, for reasons not yet completely understood, a subset of tumor cells are insensitive to the action of the drug. The development of novel agents that lack the drawbacks of the natural products is thus necessary. Here we present an overview of such efforts with focus on a new class of purine-scaffold Hsp90 inhibitors developed by rational design.

publication date

  • October 2003

Research

keywords

  • Report

Identity

Digital Object Identifier (DOI)

  • 10.2174/1568009033481778

PubMed ID

  • 14529388

Additional Document Info

start page

  • 371

end page

  • 6

volume

  • 3

number

  • 5