Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity

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• 作者：Srinivas R. Kasibhatla ; Kevin Hong ; Marco A. Biamonte ; David J. Busch ; Patricia L. Karjian ; John L. Sensintaffar ; Adeela Kamal ; Rachel E. Lough ; John Brekken ; Karen Lundgren ; Roy Grecko ; Gregg A. Tim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：June 14, 2007
• 年：2007
• 卷：50
• 期：12
• 页码：2767 - 2778
• 全文大小：166K
• 年卷期：v.50,no.12(June 14, 2007)
• ISSN：1520-4804

文摘

Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformationand maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependenton Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts.Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latentinactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide ahigh therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. Wenow report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC₅₀ of 30 = 0.009M in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumorcell lines (IC₅₀ of 30 = 0.03 M in MCF7 cells). Moreover, this class of inhibitors shows higher affinity forthe activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. Whenadministered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), whichis a compound currently in phase I/II clinical trials.