Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield, Oxford, OX1 3TA, UK.
Department of Chemistry, University of Oxford, Oxford, OX1 3QR, UK.
Nat Commun. 2022 Aug 15;13(1):4785. doi: 10.1038/s41467-022-32436-4.
Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials.
ivosidenib 是一种异柠檬酸脱氢酶 1（IDH1）R132C 和 R132H 变体抑制剂，已被批准用于治疗急性髓系白血病（AML）。由于 IDH1 R132C 的第二个位点突变导致 IDH1 R132C/S280F，出现了对ivosidenib 的耐药性。我们描述了关于 IDH1 R132C/S280F 和 R132H/S280F 变体的生化、晶体学和细胞研究，这些研究阐明了第二点耐药的机制，其中包括在 IDH1 二聚体界面处调节抑制剂结合以及改变动力学特性，从而使 2-HG 的产生相对于 IDH1 R132C 和 IDH1 R132H 更有效。重要的是，生化和细胞结果表明，通过使用替代抑制剂，包括一些目前处于 2 期临床试验的抑制剂，有可能克服 AML 患者中 S280F 介导的耐药性。
