Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-c]pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone

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• 作者：Fran莽ois Vall茅e ; Chantal Carrez ; Fabienne Pilorge ; Alain Dupuy ; Annick Parent ; Luc Bertin ; Fabienne Thompson ; Paul Ferrari ; Florence Fassy ; Annabelle Lamberton ; Anne Thomas ; Rosalia Arrebola ; St茅phane Guerif ; Alexandre Rohaut ; Victor Certal ; Jean-Marie Ruxer ; C茅cile Delorme ; Alain Jouanen ; Jacques Dumas ; Claudine Gr茅pin ; C茅cile Combeau ; H茅l猫ne Goulaouic ; Norbert Dereu ; Vincent Mikol ; Patrick Mailliet ; Herv茅 Minoux
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7206-7219
• 全文大小：1340K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4鈥?-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC₅₀ = 7.6 渭M on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an 鈥渋nduced鈥?hydrophobic pocket, 10鈥?5 脜 away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K_d = 0.35 nM on Hsp90; IC₅₀ = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.