Structure-Activity Relationships in Purine-Based Inhibitor Binding to Hsp90 Isoforms

摘要: Inhibition of the ATPase activity chaperone protein HSP90 is a potential strategy for treatment cancers. We have determined structures HSP90α N-terminal domain complexed with purine-based inhibitor, PU3, and analogs enhanced potency both in enzyme cell-based assays. The compounds induce upregulation HSP70 downregulation known client proteins Raf-1, CDK4, ErbB2, confirming that molecules inhibit cell growth by mechanism dependent on inhibition. also first structure HSP90β, PU3. allow detailed rationale to be developed observed affinity PU3 class provide structural framework design improved binding drug-like properties.