Inhibition of HSP90 with Pochoximes: SAR and Structure-Based Insights Sofia Barluenga [a] , Jean-Gonzague Fontaine [a] , Cuihua Wang [a] , Kais Aouadi [a] , Ruihong Chen [b] , Kristin Beebe [c] , Len Neckers [c] , Nicolas Winssinger [a] [a] Institut de Science et d’Ingénierie Supramoleculaires, Université de Strasbourg, CNRS (UMR7006), 8 Allée Gaspard Monge, 67000 Strasbourg (France) [b] Negenix Pharmaceuticals, 152 West 57th Street, NY 10019 (USA) [c] National Cancer Institute, Urologic Oncology Branch, 9000 Rockville Pike, Bethesda, MD 20892 (USA) 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. Graphical Abstract Fax: (+33) 3-90-24-51-12, winssinger@isis.u-strasbg.fr. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cbic.200900494. HHS Public Access Author manuscript Chembiochem. Author manuscript; available in PMC 2020 October 14. Published in final edited form as: Chembiochem. 2009 November 23; 10(17): 2753–2759. doi:10.1002/cbic.200900494. Author Manuscript Author Manuscript Author Manuscript Author Manuscript