Lactate Dehydrogenase (LDH) is an enzyme that catalyzes conversion of pyruvate to lactate. The LDH-A gene is upregulated in many cancers, supporting the high glycolytic activity observed in many tumor cells (the Warburg effect). We report the discovery, medicinal chemistry optimization, and biochemical and cellular characterization of a novel series of pyrazole-based inhibitors of human LDH. Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multi-parameter optimization enabled the discovery of compounds with potent enzymatic and cell-based inhibition of LDH. Lead compounds exhibit low nM inhibition of LDH, sub-micromolar inhibition of cellular lactate production, and inhibition of glycolysis in multiple cancer cell lines in vitro. Key features leading to cell-based activity included drug-target residence time, measured by kinetic analysis of target binding by SPR, as well as potent target engagement assessed using the cellular thermal shift assay (CETSA). Optimized analogs were found to be metabolically stable in multiple species, producing high plasma and tissue concentrations from multiple dosing regimens, thus enabling the initiation of in vivo pharmacodynamic and efficacy testing.<br/>

Discovery and characterization of cell active inhibitors of lactate dehydrogenase (LDH) using structure-based design

256th National Meeting (2018)

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