KAN0438757 is a potent and selective inhibitor of the metabolic kinase PFKFB3 with an IC50 value of 0.19μM[1]. PFKFB3 is an enzyme that plays a key role in glycolysis and is overexpressed in a variety of cancer cells[2]. KAN0438757 can also act as a selective inhibitor of PFKFB4[3].
In vitro, treatment of HCT-116, HT-29, HUVECs and normal colon epithelial cells with KAN0438757 (10-100μM) for 48 h increased cell death in a dose-dependent manner, but had little effect on normal colon epithelial cells[4]. Treatment of non-small cell lung cancer A549 cells with KAN0438757 (1-100μM) for 24-72 h significantly reduced cell viability, inhibited cell colony formation and migration, and induced DNA damage[5]. KAN0438757 (0-5μM) was treated with rat nucleus pulposus primary cells (NPP) for 24-72 h, which reduced tumor necrosis factor-α (TNF-α)-induced extracellular matrix (ECM) degradation, regulated the abnormal glycolytic energy metabolism phenotype, and had no cytotoxicity [6].
In vivo, KAN0438757 (25mg/kg) was treated by intraperitoneal injection in two pancreatitis model mice, and decreased levels of amylase and apoptosis activity were observed in both mice, inhibiting the exacerbation of fatty acid ethyl ester-induced severe acute pancreatitis (FAEE-SAP) and caerulein-induced acute pancreatitis (CAE-AP) [7].
References:
[1]Gustafsson N M S, Färnegårdh K, Bonagas N, et al. Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination[J]. Nature communications, 2018, 9(1): 3872.
[2]Jones B C, Pohlmann P R, Clarke R, et al. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux[J]. Cancer and Metastasis Reviews, 2022, 41(2): 447-458.
[3]Wang S, Bei Y, Tian Q, et al. PFKFB4 facilitates palbociclib resistance in oestrogen receptor‐positive breast cancer by enhancing stemness[J]. Cell Proliferation, 2023, 56(1): e13337.
[4]De Oliveira T, Goldhardt T, Edelmann M, et al. Effects of the novel PFKFB3 inhibitor KAN0438757 on colorectal cancer cells and its systemic toxicity evaluation in vivo[J]. Cancers, 2021, 13(5): 1011.
[5]Özdemir D, Saruhan S, Ağca C A. KAN0438757: a novel PFKFB3 inhibitor that induces programmed cell death and suppresses cell migration in non-small cell lung carcinoma cells[J]. 2023.
[6]Cao X, Wang X, Rong K, et al. Specific PFKFB3 inhibitor memorably ameliorates intervertebral disc degeneration via inhibiting NF-κB and MAPK signaling pathway and reprogramming of energy metabolism of nucleus pulposus cells[J]. Oxidative Medicine and Cellular Longevity, 2022.
[7]Ergashev A, Shi F, Liu Z, et al. KAN0438757, a novel PFKFB3 inhibitor, prevent the progression of severe acute pancreatitis via the Nrf2/HO-1 pathway in infiltrated macrophage[J]. Free Radical Biology and Medicine, 2024, 210: 130-145.
KAN0438757是一种有效的选择性代谢激酶PFKFB3抑制剂，IC50值为0.19 μM[1]。PFKFB3是一种在糖酵解中发挥关键作用的酶，并在多种癌细胞中过度表达[2]。KAN0438757也可以作为PFKFB4的选择性抑制剂[3]。
在体外，KAN0438757（10-100μM）处理HCT-116、HT-29、HUVECs和正常结肠上皮细胞48 h，剂量依赖性地增加了细胞死亡率，但对正常结肠上皮细胞的影响较小[4]。KAN0438757（1-100μM）处理非小细胞肺癌A549细胞24-72h，显著降低了细胞活力，抑制了细胞的集落形成、迁移，诱导了DNA损伤[5]。KAN0438757（0-5μM）处理大鼠髓核原代细胞（NPP）24-72h，减轻了肿瘤坏死因子-α（TNF-α）诱导的细胞外基质（ECM）降解，调节了糖酵解能量代谢表型的异常，且没有细胞毒性[6]。
在体内，KAN0438757（25 mg/kg）通过腹腔注射治疗两种胰腺炎模型小鼠，均观察到淀粉酶和细胞凋亡活性水平下降，抑制了脂肪酸乙酯诱导的重症急性胰腺炎（FAEE-SAP）和雨蛙素诱导的急性胰腺炎（CAE-AP）的恶化[7]。