A Medicinal Chemistry Perspective on Lactate Dehydrogenase: Current Status and Future Directions

Lactate dehydrogenase (LDH) plays a significant role in cancer development. LDH-A, a key enzyme in aerobic glycolysis, is highly expressed in a multitude of tumor cells and is significantly correlated with tumor proliferation. LDH-A promotes malignant tumor progression through mechanisms such as increased lactate production and accelerated glycolysis. High LDH expression is often associated with poor prognosis in tumors, making LDH and its related metabolic pathways potential targets for cancer therapy. This perspective provides a comprehensive overview of LDH in cancer, including their structure, biological role, predictive value, and therapeutic potential. Importantly, we focused on recent progress in LDH modulators, including LDH-A/LDH-B selectively inhibitors, dual-target inhibitors, PROTAC degraders, LDH inhibitors derived from natural products, and downregulators that do not directly target LDH, from the perspectives of rational design, pharmacodynamics, and pharmacokinetics. Finally, we also provide the challenges and future directions of LDH-based drug discovery.