Wright Lisa, Barril Xavier, Dymock Brian, Sheridan Louisa, Surgenor Allan, Beswick Mandy, Drysdale Martin, Collier Adam, Massey Andy, Davies Nick, Fink Alex, Fromont Christophe, Aherne Wynne, Boxall Kathy, Sharp Swee, Workman Paul, Hubbard Roderick E
Vernalis (R&D) Ltd., Granta Park, Abington, Cambridge CB1 6GB, UK.
Chem Biol. 2004 Jun;11(6):775-85. doi: 10.1016/j.chembiol.2004.03.033.
Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha 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 HSP90beta, 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.
抑制伴侣蛋白HSP90的ATP酶活性是一种治疗癌症的潜在策略。我们已经确定了HSP90α N端结构域与嘌呤类抑制剂PU3以及在酶和细胞实验中效力增强的类似物形成的复合物的结构。这些化合物诱导HSP70上调以及已知的HSP90客户蛋白Raf-1、CDK4和ErbB2下调，证实这些分子通过依赖于HSP90抑制的机制抑制细胞生长。我们还确定了与PU3复合的HSP90β N端结构域的首个结构。这些结构为观察到的PU3类化合物对HSP90的亲和力提供了详细的理论依据，也为设计具有改善结合亲和力和类药物性质的化合物提供了结构框架。
