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


Authors: Patel, H. J.; Modi, S.; Chiosis, G.; Taldone, T.
Article Title: Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment
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. © 2011 Informa UK, Ltd.
Keywords: protein phosphorylation; treatment outcome; unclassified drug; acute granulocytic leukemia; review; cisplatin; nonhuman; unspecified side effect; drug targeting; phenotype; unindexed drug; melanoma; enzyme inhibition; multiple myeloma; breast cancer; lung non small cell cancer; molecular dynamics; drug structure; enzyme activity; prostate cancer; molecular mechanics; cancer inhibition; cancer cell; heat shock protein 90 inhibitor; tanespimycin; heat shock protein 90; targeted therapy; epigallocatechin gallate; molecular interaction; kidney cancer; adenosine triphosphatase; nuclear magnetic resonance; acetylation; 5 (2,4 dihydroxy 5 isopropylphenyl) 4 (4 morpholinomethylphenyl) 3 isoxazolecarboxylic acid ethylamide; geldanamycin; radicicol; 3 (5 chloro 2,4 dihydroxyphenyl) n ethyl 4 (4 methoxyphenyl) 5 pyrazolecarboxamide; 4 [4 (1,4 benzodioxan 6 yl) 5 methyl 1h pyrazol 3 yl] 6 ethylresorcinol; cycloproparadicicol; g 3129; kf 25706; chaperone; pu h 71; ansamycin derivative; heat-shock protein 90; alvespimycin; at 13387; bibb 021; bulgarialactone b; cnf 2024; cudc 305; g 3130; herbimycin b; kw 2478; macbecin i; nvp bep800; pu 24fcl; pu 3; retaspimycin; nitrosylation
Journal Title: Expert Opinion on Drug Discovery
Volume: 6
Issue: 5
ISSN: 1746-0441
Publisher: Informa Healthcare  
Date Published: 2011-05-01
Start Page: 559
End Page: 587
Language: English
DOI: 10.1517/17460441.2011.563296
PROVIDER: scopus
PMCID: PMC3293194
PUBMED: 22400044
DOI/URL:
Notes: --- - "Export Date: 23 June 2011" - "Source: Scopus"
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MSK Authors
  1. Shanu Modi
    158 Modi
  2. Hardik Jitendra Patel
    24 Patel
  3. Gabriela Chiosis
    224 Chiosis
  4. Tony Taldone
    77 Taldone