Discovery of N-methylguanidine derivatives as a new type of potent pyruvate kinase M2 inhibitor

Lung cancer is the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for 80–85 % of all cases. Thus, while challenging, the exploration of novel therapeutic agents for NSCLC treatment is highly desirable. Pyruvate kinase M2 (PKM2) has been closely associated with disease progression and metastasis in NSCLC, making it a promising therapeutic target. Herein, we report the discovery of a series of N-methylguanidine derivatives that demonstrated potent PKM2 inhibitory activity. In particular, N′-phenanthroline-substituted N-methyl guanidine exhibited notable PKM2 inhibition. Further testing demonstrated that compound 16 exhibited excellent inhibitory effects on A549 and HCC1833 NSCLC cell lines, with IC₅₀ values of 3.36 μM and 9.20 μM, respectively. In vivo antitumor studies further showed that compound 16 significantly inhibited tumor growth in human-derived NSCLC models and mouse lung adenocarcinoma models. Based on these findings, we propose N′-phenanthroline-substituted N-methylguanidine 16 as a promising novel PKM2 inhibitor with potential therapeutic applications for NSCLC.