KAN0438757

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.