Author/Authors :
Lisa Wright، نويسنده , , Xavier Barril، نويسنده , , Brian Dymock، نويسنده , , Louisa Sheridan، نويسنده , , Allan Surgenor، نويسنده , , Mandy Beswick، نويسنده , , Martin Drysdale، نويسنده , , Adam Collier، نويسنده , , Andy Massey، نويسنده , , Nick Davies، نويسنده , , Alex Fink، نويسنده , , Christophe Fromont، نويسنده , , G. Wynne Aherne، نويسنده , , Kathy Boxall، نويسنده , , Swee Sharp، نويسنده , , Paul Workman، نويسنده , , Roderick E. Hubbard، نويسنده ,
Abstract :
Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90α N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90β, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties.
