Tumor cells rely on glycolysis for energy generation, in contrast to oxidative phosphorylation (TCA cycle) utilized by healthy cells, even in the presence of normal oxygen concentrations. Selective inhibition of the lactate dehydrogenase A (LDHA), which catalyzes the conversion of pyruvate to lactate, is believed to be beneficial in cancer therapy. Our interest in LDHA inhibitors led to the identification of 3-hydroxy-2-mercaptocyclohex-2-enone in a HTS campaign. Core change and structure-based design provided substituted 4-hydroxy-6-phenyl-5,6-dihydropyridin-2-ones with low nanomolar enzyme and low micromolar cellular potencies.  A crystal structure of an optimized molecule bound to LDHA and associated mouse PK and efficacy studies will be discussed.

Substituted 4-hydroxy-6-phenyl-5,6-dihydropyridin-2-ones as potent inhibitors of human lactate dehydrogenase A

248th National Meeting (2014)

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