National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
J Med Chem. 2020 Oct 8;63(19):10984-11011. doi: 10.1021/acs.jmedchem.0c00916. Epub 2020 Sep 27.
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement , possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, drug-target residence times, and PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition . The lead compounds, named () and (), possess desirable attributes for further studying the effect of LDH inhibition.
乳酸脱氢酶（LDH）催化丙酮酸转化为乳酸，同时将还原型烟酰胺腺嘌呤二核苷酸氧化，作为糖酵解途径的最后一步。糖酵解在癌细胞的代谢可塑性中起着重要作用，长期以来一直被认为是一个有潜力的治疗靶点。因此，LDH 的有效、选择性抑制剂代表了一种有吸引力的治疗方法。然而，迄今为止，药物还未能实现显著的靶向结合，这可能是因为该蛋白在细胞中存在的浓度非常高。我们在此报告了一项以吡唑为基础的化合物系列的优化活动，使用基于结构的设计概念，结合细胞效力、药物靶点停留时间和 PK 特性的优化，以确定具有一流抑制作用的抑制剂。先导化合物，分别命名为()和()，具有进一步研究 LDH 抑制作用的理想特性。
