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]
参考文献:
[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.
PKM2-IN-1 是一种丙酮酸激酶 M2 (PKM2) 抑制剂，IC50 为 2.95μM[5]。
在 MSC 中，增加 PKM2-IN 的浓度逐渐促进脂肪生成，证实了 PKM2 活性在 TRAF4 介导的脂肪生成分化抑制中的作用，10 μM PKM2-IN 增加了 TRAF4 过表达组的脂肪生成[1 ]。在 Huh7 细胞系中，PKM2-IN-1 抑制 CCL20 介导的 PKM2 表达和核定位，而不影响 ERK1/2 的磷酸化。此外，PKM2-IN-1 抑制 CCL20 介导的有氧糖酵解并降低 Huh7 细胞消耗葡萄糖和产生乳酸和 ATP 的能力[3]。PKM2-IN-1 减少乳酸产物和葡萄糖摄取在 Eca109 和 Ec9706 细胞[4].PKM2-IN-1 可在 HNSCC 细胞中诱导细胞毒性而不影响其糖酵解速率或耗氧量[7].PKM2-IN- 1 无 G2 期阻滞的 U87MG 神经胶质瘤细胞晚期凋亡显着增加[8]
在小鼠中，与对照组相比，PKM2-IN-1 治疗显着降低了肿瘤体积和肿瘤重量。同时，在用 PKM2-IN-1 处理的小鼠中未检测到明显的体重减轻，表明 PKM2-IN-1 不会引起任何主要器官毒性。因此，使用特定的 PKM2 抑制剂来阻断糖酵解途径和靶向癌细胞代谢是治疗 PKM2 过表达卵巢癌的一种很有前途的治疗方法[6]。在 7 日龄小鼠的心脏中， PKM2 特异性抑制剂 PKM2-IN-1 显着阻断 HRR 组心肌细胞的增殖，表明 PKM2-IN-1 完全消除了 HRR 诱导的心肌细胞增殖[2]
| Cell experiment [1]: | |
|
Cell lines |
Mesencgymal stem cells(MSCs) |
|
Preparation Method |
PKM2-IN-1 (10 mM) was dissolved in dimethyl sulfoxide (DMSO) and stored at -80℃ for subsequent experiments. MSCs were seeded into a 12-well plate and induced in adipogenic medium containing PKM2-IN-1 (10 μM). |
|
Reaction Conditions |
PKM2-IN-1 10 μM |
|
Applications |
Increasing the concentration of PKM2-IN-1 gradually promoted adipogenesis confirming the role of PKM2 activity in the TRAF4-mediated inhibition of adipogenic differentiation, 10 μM PKM2-IN-1 increased adipogenesis in the TRAF4-overexpressing group |
| Animal experiment [2]: | |
|
Animal models |
BALB/c nude mice subcutaneously injected with SK-OV-3 cells |
|
Preparation Method |
Once the tumor reached 200 cm3, the mice were randomly divided into two groups (n = 5 per group). PKM2-IN-1 (5 mg/kg body weight) dissolved in 1 ml of solvent was administered orally every 2 days for 31 days. |
|
Dosage form |
5 mg/kg PKM2-IN-1 orally every 2 days for 31 days |
|
Applications |
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. |
|
参考文献: [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]. 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. |
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