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PMID: 22400044 Published · ppublish English Journal Article

Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment.

Expert opinion on drug discovery ·Vol. 6 ·No. 5 ·2011-05-00 ·Pages 559-587

Patel HJ, Modi S, Chiosis G, Taldone T

Abstract

INTRODUCTION: Over the last 15 - 20 years, targeted anticancer strategies have focused on therapies aimed at abrogating a single malignant protein. Agents that are directed towards the inhibition of a single oncoprotein have resulted in a number of useful drugs in the treatment of cancers (i.e., Gleevec, BCR-ABL; Tarceva and Iressa, EGFR). However, such a strategy relies on the notion that a cancer cell is dependent on a single signaling pathway for its survival. The possibility that a cancer cell may mutate or switch its dependence to another signaling pathway can result in the ineffectiveness of such agents. Recent advances in the biology of heat-shock protein 90 (Hsp90) have revealed intimate details into the complexity of the chaperoning process that Hsp90 is engaged in and, at the same time, have offered those involved in drug discovery several unique ways to interfere in this process. AREAS COVERED: This review provides the current understanding of the chaperone cycle of Hsp90 and presents the multifaceted approaches used by researchers in the discovery of potential Hsp90 drugs. It discusses the phenotypic outcomes in cancer cells on Hsp90 inhibition by these several approaches and also addresses several distinctions observed among direct Hsp90 ATP-pocket competitors providing commentary on the potential biological outcomes as well as the clinical relevance of such features. EXPERT OPINION: The significantly different phenotypic outcomes observed from Hsp90 inhibition by the many inhibitors developed suggest that the clinical development of Hsp90 inhibitors would be better served by careful consideration of the pharmacokinetic/pharmacodynamic properties of individual candidates rather than a generic approach directed towards the target.

Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Patel Hardik J
Sloan Kettering Institute, Department of Molecular Pharmacology and Chemistry, NY, USA.
Modi Shanu
Chiosis Gabriela
Taldone Tony
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Article Info
Journal
Expert opinion on drug discovery
Abbr.
Expert Opin Drug Discov
ISSN
1746-045X
DOI
10.1517/17460441.2011.563296
Published
2011-05-00
Pages
559-587
Language
English
Region
England
NLM ID
101295755
PMCID
PMC3293194
Grants
NIAID NIH HHS · R21 AI090501 · United States
NIA NIH HHS · U01 AG032969-03 · United States
NCI NIH HHS · R01 CA155226 · United States
NCI NIH HHS · R21 CA158609 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · R01 CA155226-02 · United States
NIA NIH HHS · U01 AG032969 · United States
NCI NIH HHS · R01 CA172546 · United States
External Links
PubMed source DOI: 10.1517/17460441.2011.563296 PMC Full Text View journal details
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