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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Lactate dehydrogenase A (LDHA) overexpression fuels tumor growth and chemoresistance by maintaining high glycolysis.
• Targeting LDHA is a promising strategy for cancer treatment.

Purpose of the Study:

• To identify novel inhibitors of lactate dehydrogenase A (LDHA).
• To characterize the binding mechanism and site of these inhibitors.

Main Methods:

• High-throughput screening of chemical libraries.
• Biochemical assays to measure enzyme inhibition.
• Cocrystallization studies to determine protein-ligand complex structure.

Main Results:

• Phthalimide and dibenzofuran derivatives were identified as potent LDHA inhibitors.
• These inhibitors selectively target the LDHA isoenzyme.
• Cocrystallization revealed binding to a novel allosteric site on the LDH5 homotetramer.

Conclusions:

• Phthalimide and dibenzofuran derivatives represent a new class of LDHA inhibitors.
• The identified allosteric binding site offers a novel target for drug development.
• These findings may lead to new therapeutic strategies against cancer.