Development of novel human lactate dehydrogenase A inhibitors: High-throughput screening, synthesis, and biological evaluations.

Human lactate dehydrogenase A (LDHA) plays a critical role in the glycolytic process, making the enzyme an ideal of anti-cancer drug target. Herein, we report the discovery of novel potent LDHA inhibitors by screening an in-house library. The hit-to-lead modification enabled us to identify compound 24c , which inhibited LDHA activity with an EC 50 value of 90 nM, and reduced MiaPaCa-2 cancer cell proliferation with an IC 50 value of 2.1 μM. In line with the in vitro anticancer activity, 24c suppressed the tumor growth at a dose of 10 mg/kg in a MiaPaCa-2 cells xenograft model, but with little effect to the mice weight. Moreover, 24c strongly inhibited MiaPaCa-2 cell colonies formation, induced MiaPaCa-2 cell apoptosis, and arrested MiaPaCa-2 cell cycle at G2 phase. In addition, the mitochondrial bioenergetics analysis suggested that 24c could reprogram cancer cell metabolic pathways from glycolysis to oxidation phosphorylation, which verified by decreasing the extracellular acidification rates and lactate formation, and increasing oxygen consumption rate in cancer cell. All these results indicate 24c is a promising metabolic modulator for the anticancer drug development. Compound 24c exhibited a potent biochemical potency, and in vitro and in vivo anticancer activity. Image 1 • Compound 24c inhibited LDHA with an EC 50 value of 90 nM. • Compound 24c reduced MiaPaCa-2 cell proliferation with an IC 50 value of 2.1 μM. • Compound 24c suppressed tumor growth in a xenograft model. [ABSTRACT FROM AUTHOR]