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
Manchester Institute of Biotechnology, University of Manchester , Princess Street, Manchester, M1 7DN, U.K.
J Med Chem. 2016 Dec 22;59(24):11120-11137. doi: 10.1021/acs.jmedchem.6b01320. Epub 2016 Dec 5.
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.
针对突变型（R132H）异柠檬酸脱氢酶IDH1对135万种化合物进行的高通量联合筛选，鉴定出了一系列新型抑制剂。对结合配体晶体结构的解析表明，这些抑制剂在IDH1（R132H）先前确定的变构位点呈现出一种新型结合模式。该信息指导了该系列化合物的优化，产生了具有良好细胞活性的亚微摩尔级酶抑制剂。令人鼓舞的是，该系列中的一种化合物在体外可诱导原发性人IDH1 R132H急性髓系白血病细胞发生髓系分化。
