PFK-015 is a potent and selective inhibitor of PFKFB3 with an IC50 value of 110nM[1]. As a key regulator of glycolytic metabolism, PFK-015 disrupts fructose-2,6-bisphosphate production and demonstrates significant anti-proliferative effects across multiple tumor cell lines[2]. The compound also induces autophagy and exhibits synergistic activity with chemotherapeutic agents in vivo[3].
In Peripheral blood mononuclear cells treatment with PFK-015(10μM; 80min) during IFN-γ-induced macrophage polarization reduced the expression of M1 surface markers CD80, iNOS, and HLA-DR[4]. In the 786-O and OS-RC-2 cell lines, the expression levels of glycolytic regulatory enzymes, key enzymes, and PD-L1 decreased after the addition of the PFKFB3 inhibitor PFK-015(10μM; 24h)[5].
In Lewis lung carcinoma (LLC)-bearing mice, PFK-015(25mg/kg; iv; every 3 days for 4 doses） inhibits the growth of Lewis lung carcinoma (LLC) xenografts by mediating the depletion of tumor-associated fructose-2,6-bisphosphate (F26BP), which consequently triggers apoptotic signaling and suppresses pulmonary metastasis of the subcutaneous tumors[6]. In the Hu-NOG mouse model, PFK-015(25mg/kg; ip; 21d）combined with PD-1 mAb therapy significantly inhibits tumor growth in human PBMC-engrafted NOG mice[7].
References:
[1].Clem B, Tapolsky G H, O'Neal J, et al. Characterization of a novel small molecule antagonist of 6-phosphofructo-2-kinase that suppresses glucose metabolism and tumor growth[J]. Cancer Research, 2011, 71(8_Supplement): 2825-2825.
[2].Ling X, Liu L, Jiang A, et al. PFKFB3 promotes endometriosis cell proliferation via enhancing the protein stability of β-catenin[J]. Molecular and Cellular Endocrinology, 2024, 579: 112083.
[3].Brooke D G, van Dam E M, Watts C K W, et al. Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2, 6-bisphosphatase 3 (PFKFB3)[J]. Bioorganic & medicinal chemistry, 2014, 22(3): 1029-1039.
[4].Chen R, Wang J, Dai X, et al. Augmented PFKFB3-mediated glycolysis by interferon-γ promotes inflammatory M1 polarization through the JAK2/STAT1 pathway in local vascular inflammation in Takayasu arteritis[J]. Arthritis research & therapy, 2022, 24(1): 266.
[5].Yu Y, Liang Y, Li D, et al. Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment[J]. Cell Death Discovery, 2021, 7(1): 15.
[6].Clem B F, O'Neal J, Tapolsky G, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer[J]. Molecular cancer therapeutics, 2013, 12(8): 1461-1470.
[7].Zheng J B, Wong C W, Liu J, et al. Glucose metabolism inhibitor PFK-015 combined with immune checkpoint inhibitor is an effective treatment regimen in cancer[J]. Oncoimmunology, 2022, 11(1): 2079182.
PFK-015是一种高效、选择性的PFKFB3抑制剂，其IC₅₀值为110nM[1]。作为糖酵解代谢的关键调节因子，PFK-015通过干扰果糖-2,6-二磷酸的生成，在多种肿瘤细胞系中表现出显著的抗增殖作用[2]。该化合物还能诱导细胞自噬，并在体内与化疗药物展现出协同抗肿瘤活性[3]。
在外周血单核细胞中，使用PFK-015（10μM；80min）处理可干扰IFN-γ诱导的巨噬细胞极化，降低M1型表面标志物CD80、iNOS和HLA-DR的表达[4]。在786-O和OS-RC-2细胞系中，加入PFKFB3抑制剂PFK-015（10μM；24h）后，糖酵解调节酶、关键酶及PD-L1的表达水平均有所下降[5]。
在Lewis肺癌荷瘤小鼠模型中，PFK-015（25mg/kg；iv；每3天一次，共4次）通过介导肿瘤相关果糖-2,6-二磷酸的耗竭，进而激活凋亡信号通路，抑制皮下移植瘤的生长并减少其肺转移[6]。在Hu-NOG小鼠模型中，PFK-015（25mg/kg；ip；21d）与PD-1单克隆抗体联合治疗，可显著抑制人源PBMC重建NOG小鼠中的肿瘤生长[7]。