Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).

We report the discovery and medicinal chemistryoptimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screeningparadigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compoundssuch as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compoundswas demonstrated using the cellular thermal shift assay(CETSA), and drug–target residence timewas determined via SPR. Analysis of these data suggests that drug–target residence time(off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.