J Med Chem. 2018 Aug 9;61(15):6647-6657. doi: 10.1021/acs.jmedchem.8b00305. Epub 2018 Jul 30.
IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive α,β-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.
IDH1 在许多代谢过程中起着关键作用，并且在细胞应激条件下充当细胞溶质 NADPH 的主要来源。然而，报道的野生型 IDH1 的抑制剂很少。在这里，我们介绍了两种新型野生型 IDH1 抑制剂的发现和生化特性。此外，我们还介绍了这些新型小分子 IDH1 结合口袋的首次配体结合晶体学特征。重要的是，NADPH 竞争性的α，β-不饱和烯酮 1 通过活性位点 H315 形成独特的共价键。由于很少有小分子被证明与组氨酸残基发生共价反应，这些数据支持了一种未充分利用的策略，用于可逆共价小分子设计的潜在效用。
