A hallmark of cancer cells' altered metabolism is their ability to rapidly convert glucose to lactate in normoxic conditions via a process termed aerobic glycolysis. The enzyme LDH catalyzes the final step of glycolysis - the inter-conversion of pyruvate and lactate � and has been proposed to be a potential cancer target. However, the high abundance of cellular LDHA as well as the highly hydrophilic nature of its catalytic site presents significant challenges to the development of inhibitors useful for in vivo testing. Here we report on the structure-based discovery of substituted 4-hydroxy-5,6-dihydropyran-2-one inhibitors of LDHA with low nanomolar biochemical and single-digit micromolar cellular potencies. Crystal structures of these molecules bound to LDHA revealed distinct sub-pockets contributing to binding affinity as well as a close coupling between the binding mode and small molecule conformational preference. Inhibition of LDHA significantly enhanced the anti-proliferation activity of antimycin (a mitochondria inhibitor) when tested in non-glycolytically dependent cells.

Substituted 4-hydroxy-5,6-dihydropyran-2-one as potent inhibitors of human lactate dehydrogenase A

248th National Meeting (2014)

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