Inhibition of HSP90 with pochoximes: SAR and structure-based insights.
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.
Institut de Science et d'Ingénierie Supramoleculaires, Université de Strasbourg, CNRS (UMR7006), 8 Allée Gaspard Monge, 67000 Strasbourg, France.
Sofia
S
Barluenga
Jean-Gonzague
JG
Fontaine
Cuihua
C
Wang
Kais
K
Aouadi
Ruihong
R
Chen
Kristin
K
Beebe
Len
L
Neckers
Nicolas
N
Winssinger
D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D010091:Oximes; D054852:Small Molecule Libraries; C035359:monorden