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Inhibition of HSP90 with Pochoximes: SAR and Structure-Based Insights

Barluenga, Sofia
Fontaine, Jean-Gonzague
Wang, Cuihua
Aouadi, Kais
Chen, Ruihong
Beebe, Kristin
Neckers, Len
Published in ChemBioChem. 2009, vol. 10, no. 17, p. 2753-2759
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.
Keywords Hsp90inhibitorspochoximeradicicolstructure–activity relationships
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BARLUENGA, Sofia et al. Inhibition of HSP90 with Pochoximes: SAR and Structure-Based Insights. In: ChemBioChem, 2009, vol. 10, n° 17, p. 2753-2759. doi: 10.1002/cbic.200900494

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Deposited on : 2012-12-18

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