Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells

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• 作者：Stuart Jones ; Jonathan Ahmet ; Kelly Ayton ; Matthew Ball ; Mark Cockerill ; Emma Fairweather ; Nicola Hamilton ; Paul Harper ; James Hitchin ; Allan JordanColin Levy ; Ruth Lopez ; Eddie McKenzie ; Martin Packer ; Darren Plant ; Iain Simpson ; Peter Simpson ; Ian Sinclair ; Tim C. P. Somervaille ; Helen Small ; Gary J. Spencer ; Graeme Thomson ; Michael Tonge ; Ian Waddell ; Jarrod Walsh ; Bohdan Waszkowycz ; Mark WigglesworthDaniel H. Wiseman ; Donald Ogilvie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：11120-11137
• 全文大小：1032K
• ISSN：1520-4804

文摘

A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.