A hallmark of cancer cells’ altered metabolism is their ability to rapidly convert glucose to lactate under normal oxygen conditions via a process termed aerobic glycolysis (Warburg effect). The lactate dehydrogenase (LDHA) enzyme catalyzes the final step of glycolysis - the conversion of pyruvate to lactate – and has thus been considered a vital therapeutic target for invasive cancers. However, the high abundance of cellular LDHA as well as the highly hydrophilic nature of its catalytic site present significant challenges to the development of inhibitors suitable for <i>in vivo</i> testing. Here we report the discovery and structure-guided optimization of a series of substituted 4-hydroxy-5,6-dihydropyran/dihydropyridin-2-one inhibitors that exhibit low nanomolar biochemical and single-digit micromolar cellular potencies. The inhibitors were also over 1000-fold more selective toward LDHA relative to the structurally closely-related malate dehydrogenase enzymes. Crystal structures of the inhibitors in complex with LDHA revealed distinct sub-pockets contributing to binding affinity as well as a close coupling between small molecule conformational preferences and their binding modes. The optimization efforts afforded potent cell-active LDHA inhibitors with acceptable metabolic stability and oral bioavailability in mice, a combination which is unprecedented in LDHA inhibitor field.

Discovery and structure-based optimization of substituted 4-hydroxy-5,6-dihydropyran/dihydropyridin-2-ones as potent inhibitors of human lactate dehydrogenase A

251st National Meeting (2016)

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