Recent progress in the development of small molecule pyruvate kinase M2 inhibitors: 2020–2025

Pyruvate kinase M2 (PKM2) is a central regulator of glycolysis and anabolic metabolism, playing a pivotal role in cancer cell proliferation. Its multifunctional nature and involvement in various disease pathways make it an attractive therapeutic target, especially in oncology and inflammation. This review summarizes research over the past five years on small molecule PKM2 inhibitors. Activators of PKM2 promote the tetrameric form of PKM2, enhancing oxidative phosphorylation and reversing the Warburg effect. In contrast, inhibitors like micheliolide (MCL) and isoselenazolium compounds disrupt PKM2's non-metabolic roles, inducing tumor cell death. Literature was selected through focused searches on PKM2-targeted therapies in cancer, inflammation, and neurodegeneration, with attention to recent advances in structural biology, computational modeling, and high-throughput screening. PKM2 modulators show promise across a range of diseases beyond cancer, including inflammatory and neurodegenerative conditions. However, challenges in isoform selectivity, toxicity, and clinical translation persist. Although, no PKM2 inhibitors have entered and succeeded in clinical trials, continued research and technological advances are essential to unlock PKM2's full therapeutic potential and guide its development into safe, effective clinical treatments.