生物活性

• 描述3PO is a potent PFKFB3 inhibitor with Ki value of 25μM. It suppressed glycolytic flux and was cytostatic to neoplastic cells. 3PO inhibited recombinant PFKFB3 activity, suppressed glucose uptake, and decreased the intracellular concentration of Fru-2,6-BP, lactate, ATP, NAD⁺, and NADH. 3PO markedly attenuated the proliferation of several human malignant hematopoietic and adenocarcinoma cell lines with IC50 values ranging in 1.4-24μM and is selectively cytostatic to ras-transformed human bronchial epithelial cells relative to normal human bronchial epithelial cells. Intraperitoneal administration of 3PO at dose of 70mg/kg to tumor-bearing mice suppressed growth of tumor xenografts, including Lewis lung carcinoma, MDA-MB231 and HL-60, as well as markedly reduced the intracellular concentration of Fru-2,6-BP, glucose uptake, and growth of established tumors in vivo^[3]. Blockade of PFKFB3 by 3PO reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. Also it suppressed vascular hyperbranching induced by inhibition of Notch or VEGFR1 and amplified the antiangiogenic effect of VEGF blockade^[4].
• 作用机制3PO may bind the Fru-6-P binding site and inhibit PFKFB3 through a mixed inhibition mechanism in both competitive and uncompetitive manner.^[3]

• 动物研究
  剂量	Mice: 0.07 mg/g[3] (i.p.), 50 mg/kg[4] (i.p.), 70 mg/kg[5] (i.p.)
  给药途径	i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00641160	Nonhematologic Malignancies	Phase 1	Unknown	November 2008	United States, Texas ... more >> Texas Oncology PA; Sammons Cancer Center Dallas, Texas, United States, 75246 Collapse <<
  NCT00423982	Prosthesis-related Infections ... more >> Staphylococcal Infections Collapse <<	Phase 4	Unknown	December 2014	Norway ... more >> Buskerud Central Hospital Drammen, Norway, 3004 Elverum Hospital Elverum, Norway, 2408 Martina Hansen Hospital Gjettum, Norway, 1346 Ringerike Hospital Hønefoss, Norway, 3504 Lillehammer Hospital Lillehammer, Norway, 2609 Oslo University Hospital, Ulleval Oslo, Norway, 0407 Asker and Bærum Hospital Rud, Norway, 1309 St.Olav Hospital Trondheim, Norway, 7030 Collapse <<
  NCT02744638	Bacterial Vaginosis	Not Applicable	Completed	-	Germany ... more >> CRC Clinical Research Center Kiel Kiel, Schleswig-Holstein, Germany, 24118 Collapse <<

• 更多
• 参考文献

• [1] Clem B, Telang S, 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] Schoors S, De Bock K, et al. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab. 2014 Jan 7;19(1):37-48.

  [3] Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther. 2008 Jan;7(1):110-20. doi: 10.1158/1535-7163.MCT-07-0482. PMID: 18202014.

  [4] Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquière B, Cauwenberghs S, Kuchnio A, Wong BW, Quaegebeur A, Goveia J, Bifari F, Wang X, Blanco R, Tembuyser B, Cornelissen I, Bouché A, Vinckier S, Diaz-Moralli S, Gerhardt H, Telang S, Cascante M, Chesney J, Dewerchin M, Carmeliet P. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab. 2014 Jan 7;19(1):37-48. doi: 10.1016/j.cmet.2013.11.008. Epub 2013 Dec 12. PMID:24332967.