Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A

Lactate
dehydrogenase A (LDHA) is frequently overexpressed in tumors,
thereby sustaining high glycolysis rates, tumor growth, and chemoresistance.
High-throughput screening resulted in the identification of phthalimide
and dibenzofuran derivatives as novel lactate dehydrogenase inhibitors,
selectively inhibiting the activity of the LDHA isoenzyme. Cocrystallization
experiments confirmed target engagement in addition to demonstrating
binding to a novel allosteric binding site present in all four LDHA
subunits of the LDH5 homotetramer.