Targeting Lactate Dehydrogenase-B as a Strategy to Fight Cancer: Identification of Potential Inhibitors by In Silico...

Area of Science:

• Biochemistry
• Enzymology
• Cancer Biology

Background:

• Lactate dehydrogenase (LDH) is crucial in cellular metabolism, converting lactate to pyruvate.
• LDH-A isoform is a known target in cancer therapy due to its role in the Warburg effect.
• LDH-B isoform's role in breast and lung cancer necessitates research into its specific inhibitors.

Purpose of the Study:

• To identify small-molecule compounds that specifically inhibit the LDH-B isoform.
• To explore potential dual-acting therapeutic agents for cancer treatment.

Main Methods:

• In silico screening of commercially available compounds for LDH-B inhibitory activity.
• In vitro evaluation of top candidate compounds.
• Uncompetitive inhibition mechanism determination.
• Molecular dynamics simulations to support findings.

Main Results:

• Eight compounds were identified computationally as potential LDH-B inhibitors.
• Tucatinib and capmatinib demonstrated in vitro inhibition of LDH-B.
• Both drugs exhibited an uncompetitive inhibition mechanism against LDH-B.
• Molecular dynamics studies corroborated the inhibitory effects.

Conclusions:

• Tucatinib and capmatinib, approved for breast and lung cancer respectively, also inhibit LDH-B.
• These findings suggest a potential dual-targeting mechanism for these drugs in cancer therapy.
• The study provides a foundation for developing more potent and specific LDH-B inhibitors.