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Inhibition of HSP90 with pochoximes: SAR and structure-based insights.

ABSTRACT: The pochoximes, based on the radicicol pharmacophore, are potent inhibitors of heat shock protein 90 (HSP90) that retain their activity in vivo. Herein we report an extended library that broadly explores the structure-activity relationship (SAR) of the pochoximes with four points of diversity. Several modifications were identified that afford improved cellular efficacy, new opportunities for conjugation, and further diversifications. Cocrystal structures of pochoximes A and B with HSP90 show that pochoximes bind to a different conformation of HSP90 than radicicol and provide a rationale for the enhanced affinity of the pochoximes relative to radicicol and the pochonins.

SUBMITTER: Barluenga S

PROVIDER: S-EPMC7556317 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Inhibition of HSP90 with pochoximes: SAR and structure-based insights.

Barluenga Sofia S Fontaine Jean-Gonzague JG Wang Cuihua C Aouadi Kais K Chen Ruihong R Beebe Kristin K Neckers Len L Winssinger Nicolas N

Chembiochem : a European journal of chemical biology 20091101 17

The pochoximes, based on the radicicol pharmacophore, are potent inhibitors of heat shock protein 90 (HSP90) that retain their activity in vivo. Herein we report an extended library that broadly explores the structure-activity relationship (SAR) of the pochoximes with four points of diversity. Several modifications were identified that afford improved cellular efficacy, new opportunities for conjugation, and further diversifications. Cocrystal structures of pochoximes A and B with HSP90 show tha ...[more]

PMID: 19856365

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