The objective of the work proposed herein is to develop novel inhibitors of the human enzyme lactate dehydrogenase A (LDH-A). LDH-A catalyzes the conversion of pyruvate to lactate, the final step in the glycolytic pathway. Although a few LDH-A inhibitors have been reported, no compounds are suitable for further development (ie, potent, specific, synthetically tractable, and metabolically stable). In preliminary results w have discovered a novel class of LDH-A inhibitors, the N-hydroxyindoles (NHIs). These compounds inhibit LDH-A in vitro, inhibit tumor growth in vivo, and we have collected multiple lines of evidence indicating these compounds inhibit LDH-A in cells. We now wish to utilize this novel research tool, the NHI- based LDH-A inhibitors, to exploit the Warburg effect as a potential anticancer strategy. The Warburg effect is the tendency of cancer cells to rely on aerobic glycolysis instead of oxidative phosphorylation for energy production. Multiple lines of genetic data suggests that LDH-A inhibition could selectively induce death in cancer cells, and indeed as described in the preliminary results we have conducted multiple shRNA experiments that strongly suggest the inhibition of LDH-A will be an effective anticancer stragegy. Through the work proposed we intend to develop more potent NHIs as LDH-A inhibitors, assess their effect on cancer cells in culture, and evaluate them in murine tumor models. Through this work we intend to demonstrate that the inhibition of LDH-A is a tractable anticancer strategy, and to identify candidate experimental therapeutics.
The inhibition of Lactate Dehydrogenase A (LDH-A) is a promising strategy for the treatment of cancer, unfortunately, no suitable LDH-A inhibitors exist. Described in this proposal is the development of a novel class of LDH-A inhibitors recently discovered by the PIs. These compounds will be optimized through chemical synthesis, tested for their effects on cancer cells in culture, and evaluated in two murine tumor models.
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