PKM2-IN-1

PKM2-IN-1 is a selective pyruvate kinase M2 (PKM2) inhibitor (IC₅₀=2.95μM). PKM2-IN-1 inhibits PKM2 enzyme activity, blocks the conversion of phosphoenolpyruvate to pyruvate, reduces lactate production and interferes with the Warburg effect, decreases ATP production and inhibits Akt/mTOR signaling pathway to reduce tumor cell proliferation. PKM2-IN-1 can be used in research related to cancers (non-small cell lung cancer, ovarian cancer, glioma, etc.) and Parkinson's disease metabolism^[1-4].

In vitro, treatment with PKM2-IN-1 (1-4μM) for 48h in normal L929 cells caused a concentration-dependent reduction in collagen production, enhanced activation of P16, P21, P53, Caspase-3 and ATM, and impaired cell viability^[5]. Treatment with PKM2-IN-1 (5μM) for 72h in HEK-293T cells co-transfected with FTO and HK1 abolished FTO/HK1-mediated upregulation of RANK protein^[6]. Treatment with PKM2-IN-1 (10μM) for 24h in BRG1-overexpressing non-small cell lung cancer cells caused BRG1 to lose its inhibitory effect on glycolysis and its ability to attenuate cell proliferation^[7].

In vivo, BALB/c mice subcutaneously inoculated with A549 cells received intraperitoneal injections of PKM2-IN-1 at 3mg/kg every other day for 15 days, PKM2-IN-1 attenuated A549 tumor xenograft growth and reduced Ki67 proliferation marker expression in tumor tissues^[8]. C57BL/6 mice and A30P mouse Parkinson's disease models received oral gavage of PKM2-IN-1 at 50mg/kg for 5 consecutive days, PKM2-IN-1 improved behavioral deficits and prevented dopaminergic neuron loss in the substantia nigra pars compacta^[9]. C57BL/6 mice subjected to unilateral ischemia-reperfusion injury received oral gavage of PKM2-IN-1 at 5mg/kg every other day starting from postoperative day 1 or day 7 until day 14, PKM2-IN-1 inhibited kidney atrophy and reduced the long-axis cross-sectional area of the kidney^[10].

References:

[1] Park JH, Kundu A, et al. Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces Autophagic Cell Death through Disruption of the Glycolysis Pathway in Ovarian Cancer Cells. Int J Biol Sci. 2021 May 5;17(8):1895-1908.

[2] Leng L, Yuan Z, Pan R, et al. Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance. Nat Metab. 2022 Oct;4(10):1287-1305.

[3] Ning X, Qi H, Li R, et al. Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase. Eur J Med Chem. 2017 Sep 29;138:343-352.

[4] Su G, Liu J, Duan C, et al. Enteric coronavirus PDCoV evokes a non-Warburg effect by hijacking pyruvic acid as a metabolic hub. Redox Biol. 2024;71:103112.

[5] Jia S, Shi N, Lu M, et al. M2 macrophages promote PKM2 production in fibroblasts to alleviate UVB-induced photoaging. Cell Cycle. 2025;24(5-8):86-102.

[6] Qian Y, Wu J, Yang W, et al. FTO-associated osteoclastogenesis promotes alveolar bone resorption in apical periodontitis male rat via the HK1/USP14/RANK pathway. Nat Commun. 2025 Feb 11;16:1519.

[7] Zhan W, Zhang H, She X, et al. BRG1 inhibits glycolysis by promoting SHP1-mediated dephosphorylation of PKM2 in non-small cell lung cancer. Oncogenesis. 2025;14:32.

[8] Wang K, Lu H, Wang X, et al. Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC. Front Pharmacol. 2023;14:1200538.

[9] Lian B, Zhang J, Yin X, et al. SIRT1 improves lactate homeostasis in the brain to alleviate parkinsonism via deacetylation and inhibition of PKM2. Cell Rep Med. 2024 Aug 20;5(8):101684.

[10] Kosakai W, Inoue T, Sato T, et al. PKM2 inhibitor suppresses kidney fibrogenesis by disrupting YAP-TEAD-CCN2 transcriptional signaling following ischemia-reperfusion injury. J Biol Chem. 2026;302(1):111029.