3PO is a small-molecule inhibitor of PFKFB3, a key enzyme involved in glycolysis with IC50 values ranging from 1.4 to 24µM and a Ki value of 25 ± 9μM. By inhibiting PFKFB3, 3PO reduces the levels of Fru-2,6-BP, lactate, ATP, NAD+, and NADH within cells[1]. 3PO has gained significant attention for its potential applications in cancer research and metabolic studies[2][3][4][5][6][7].
In vitro, 3PO (10µM) treated bladder cancer cells lines (5637, HT1197, HT1376, RT4, SW780, T24, TCCSUP, and UM-UC-3) for 72h reduced cell growth and also decreased lactate production and acidification of the culture medium, indicating its inhibitory effects on glycolysis[2]. 3PO (20μM) pretreatment of HUVEC for 30 min significantly reduced IKKα/β and JNK phosphorylation, thereby inhibiting inflammatory signaling induced by subsequent TNF (1ng/mL) or IL-1β (1ng/mL) stimulation[3]. 3PO (0.1–1.0µg/mL) incubated human umbilical vein endothelial cells (HUVECs) for 24, 48, or 72h reduce the ATP flow by cutting down the energy transform, thereby inhibiting tumor angiogenesis and assisting ROS to promote the early withering of tumor cells[4].
In vivo, 3PO (38-50mg/kg) injected intraperitoneally into choroidal neovascularization (CNV) mouse model amplified the antiangiogenic activity and dose dependently reduced the CNV lesion volume[5]. 3PO (150mg/kg) administered via intraperitoneal injection in mouse model after myocardial infarction (MI) once every other day for 28 days effectively reduced fibrosis and improved adverse cardiac remodeling[6]. 3PO in the cross-linked sodium lipoic acid vesicle (3PO@cLANa) (156.3mg/kg, containing 1.5mg/kg 3PO) administrated into B16F10 melanoma tumor model via intratumoral injection at days 1, 4, and 7 exerted antitumor and antimetastasis effects[7].
References:
[1] Clem B, Telang S, Clem A, et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.Mol Cancer Ther. 2008 Jan;7(1):110-20.
[2] Lea M A, Altayyar M, desBordes C. Inhibition of Growth of Bladder Cancer Cells by 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one in Combination with Other Compounds Affecting Glucose Metabolism.Anticancer Res. 2015 Nov;35(11):5889-99.
[3] Wik J A, Peter Lundbäck P, Poulsen C L,et al. 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3. PLoS One. 2020 Mar 4;15(3):e0229395.
[4] Li S Y, Ding H, Chang J H, et al. Sm/Co-Doped Silica-Based Nanozymes Reprogram Tumor Microenvironment for ATP-Inhibited Tumor Therapy.Adv Healthc Mater. 2023 Sep; 12(24):e2300652.
[5] Schoors S, Bock K D, Cantelmo A R, et al. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis.Cell Metab. 2014 Jan 7;19(1):37-48.
[6] Yang Q, Zong X, Zhuang L F, et al. PFKFB3 Inhibitor 3PO Reduces Cardiac Remodeling after Myocardial Infarction by Regulating the TGF-β1/SMAD2/3 Pathway. Biomolecules. 2023 Jul 3;13(7):1072.
[7] Lai H J, Wu X, Tan J.et al. Regulation of tumor lactate metabolism by targeting glycolysis and mitochondrial OXPHOS for tumor metastasis inhibition. J.Industrial & Engineering Chemistry Research. 2023 June,62(27)
3PO是参与糖酵解的关键酶PFKFB3的小分子抑制剂，IC50值为1.4至24µM， Ki值为25±9μM。通过抑制PFKFB3, 3PO降低了细胞内Fru-2、6-BP、乳酸、ATP、NAD+和NADH的水平[1]。3PO在癌症研究和代谢疾病研究中的潜在应用[2][3][4][5][6][7]。
在体外，3PO（10µM）作用于膀胱癌细胞株（5637、HT1197、HT1376、RT4、SW780、T24、TCCSUP和UM-UC-3） 72h后，细胞生长减少，乳酸生成减少，培养基酸化减少，表明其对糖酵解有抑制作用[2]。3PO（20μM）预处理TNF（1ng/mL）或IL-1β (1ng/mL)刺激人脐静脉内皮细胞（HUVEC） 30min，通过降低IKKα/β和JN的磷酸化，抑制IL-1β和TNF诱导的炎症信号传导[3]。3PO（0.1-1.0µg/mL）在人脐静脉内皮细胞（HUVECs）中孵育24、48、72h，通过减少能量转化减少ATP流动，从而抑制肿瘤血管生成，协助ROS促进肿瘤细胞早期枯萎[4]。
在体内，3PO （38-50mg/kg）腹腔注射到脉络膜新生血管（CNV）小鼠模型中，可增强其抗血管生成活性，并剂量依赖性地减少CNV病变体积[5]。心肌梗死（MI）后小鼠模型腹腔注射3PO (150mg/kg)，每隔一天1次，连用28天，可有效减少纤维化，改善不良心脏重构[6]。3PO在交联的硫辛酸钠囊泡中（3PO@cLANa）中（156.3mg/kg，含1.5mg/kg 3PO）于第1、4、7天通过瘤内注射给药B16F10黑色素瘤模型，可以发挥抗肿瘤和抗转移作用[7]。