PKM2-IN-1 (Synonyms: Compound 3K, MDK4882, PKM2-IN-1, Pyruvate Kinase M2 Inhibitor)

PKM2-IN-1 is a pyruvate kinase M2 (PKM2) inhibitor with an IC₅₀ of 2.95μM^[5].

In MSCs, Increasing the concentration of PKM2-IN gradually promoted adipogenesis confirming the role of PKM2 activity in the TRAF4-mediated inhibition of adipogenic differentiation, 10 μM PKM2-IN increased adipogenesis in the TRAF4-overexpressing group^[1]. In the Huh7 cell line, PKM2-IN-1 inhibited CCL20-mediated PKM2 expression and nuclear localization without affecting the phosphorylation of ERK1/2. Furthermore, PKM2-IN-1 inhibited CCL20-mediated aerobic glycolysis and reduced the ability of Huh7 cells to consume glucose and produce lactate and ATP^[3].PKM2-IN-1 decreased lactate product and glucose uptake in Eca109 and Ec9706  cells^[4].PKM2-IN-1 can induce cytotoxicity in HNSCC cells without affecting their glycolysis rate or oxygen consumption^[7].PKM2-IN-1 highly increased late apoptosis in U87MG glioma cells without G2-phase arrest^[8]

In mice, PKM2-IN-1 treatment markedly decreased the tumor volume and tumor weight, compared with the control group. Meanwhile, no significant weight reduction was detected in the mouse treated with PKM2-IN-1, suggesting that PKM2-IN-1 did not cause any major organ toxicity. Thus, use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer^[6].In hearts of 7-day-old mice, PKM2-specific inhibitor PKM2-IN-1 significantly blocked the proliferation of cardiomyocytes in HRR groups, indicating HRR-induced proliferation of cardiomyocytes was fully abolished by PKM2-IN-1^[2]

References:
[1]: Cen S, Li J, et,al. TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2. EBioMedicine. 2020 Apr;54:102722. doi: 10.1016/j.ebiom.2020.102722. PMID: 32268273; PMCID: PMC7191261.
[2]: Tan J, Yang M, et,al. Moderate heart rate reduction promotes cardiac regeneration through stimulation of the metabolic pattern switch. Cell Rep. 2022 Mar 8;38(10):110468. doi: 10.1016/j.celrep.2022.110468. PMID: 35263588.
[3]: Yuan Q, Zhang J, et,al. MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation. J Pathol. 2022 Apr;256(4):414-426. doi: 10.1002/path.5856. Epub 2022 Jan 27. PMID: 34927243.
[4]: Li S, Huang P, et,al. Dihydroartemisinin represses esophageal cancer glycolysis by down-regulating pyruvate kinase M2. Eur J Pharmacol. 2019 Jul 5;854:232-239. doi: 10.1016/j.ejphar.2019.04.018. Epub 2019 Apr 17. PMID: 31004604.
[5]: Ning X, Qi H, 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. doi: 10.1016/j.ejmech.2017.06.064. Epub 2017 Jun 29. PMID: 28688274.
[6]: 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. doi: 10.7150/ijbs.59855. PMID: 34131394; PMCID: PMC8193271.
[7]:Boschert V, Teusch J, et,al. PKM2 Modulation in Head and Neck Squamous Cell Carcinoma. Int J Mol Sci. 2022 Jan 11;23(2):775. doi: 10.3390/ijms23020775. PMID: 35054968; PMCID: PMC8775697.
[8]:Park JH, Lee JS, et,al. PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity. In Vivo. 2022 Mar-Apr;36(2):694-703. doi: 10.21873/invivo.12755. PMID: 35241524; PMCID: PMC8931915.