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

作者：Jones Stuart; Ahmet Jonathan; Ayton Kelly; Ball Matthew; Cockerill Mark; Fairweather Emma; Hamilton Nicola; Harper Paul; Hitchin James; Jordan Allan^*; Levy Colin; Lopez Ruth; McKenzie Eddie; Packer Martin; Plant Darren; Simpson Iain; Simpson Peter; Sinclair Ian; Somervaille Tim C P; Small Helen; Spencer Gary J; Thomson Graeme; Tonge Michael; Waddell Ian; Walsh Jarrod; Waszkowycz Bohdan; Wigglesworth Mark; Wiseman Daniel H; Ogilvie Donald

来源：Journal of Medicinal Chemistry, 2016, 59(24): 11120-11137.

DOI：10.1021/acs.jmedchem.6b01320

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.

• 出版日期2016-12-22