PKM2 Inhibitor(University of Shanghai for Science and Technology)

Fibrosis progressively impairs organ function and drives the progression of chronic kidney disease (CKD), for which effective targeted therapies are lacking. Although metabolic reprogramming toward glycolysis promotes fibrosis, the molecular link between metabolic shifts and transcriptional control in CKD and its therapeutic potential has not yet been established. In this study, we demonstrate that pyruvate kinase M2 (PKM2) orchestrates renal fibrosis via nuclear translocation and interaction with the Yes-associated protein (YAP) and beta-catenin (β-catenin) transcriptional networks. Using unilateral ischemia-reperfusion injury mouse models and human renal tubular epithelial cells, we revealed that pharmacological inhibition and genetic knockdown of PKM2 markedly attenuate renal atrophy and the expression of fibrotic markers, including cellular communication network factor 2. Mechanistically, compound 3k inhibited the nuclear translocation of PKM2 and YAP, thereby suppressing TEA domain transcription factor (TEAD)-mediated communication network factor 2 transcription. Similarly, siRNA-mediated silencing of PKM2 further confirmed the inhibition of YAP-TEAD signaling. Furthermore, co-immunoprecipitation confirmed that PKM2 forms complexes with YAP and β-catenin, integrating metabolic and transcriptional regulation. Our findings provide direct evidence that PKM2 promotes fibrosis in CKD through its role as a transcriptional cofactor rather than via its enzymatic activity. Notably, PKM2 inhibition by compound 3k remained effective even with delayed intervention, suggesting clinical translatability. Overall, these findings highlight PKM2 as a key integrator of metabolic and transcriptional reprogramming in kidney fibrosis and provide crucial preclinical evidence supporting PKM2-targeted strategies in CKD.

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.