PFK-015

PFK-015 is a potent and selective inhibitor of PFKFB3 with IC50 value of 207 nM [1].

6-phosphofructo-2-kinase (PFKFB3) is an enzyme that is encoded by the PFKFB3 gene in humans. PFKFB3 is a direct transcriptional target of HIF-α and is activated by oncogenic AKT and Ras and stabilized by the loss of the tumor suppressor PTEN via suppressive effects on APC/Cdh1-mediated ubiquitination [1].

PFK-015 is a potent and selective PFKFB3 inhibitor. In H522 lung adenocarcinoma and Jurkat cell lines, PFK15 exhibited cytotoxic effects with IC50 values of 2.42 and 0.72 μM in Jurkat and H522, respectively. Also, PFK15 reduced glucose uptake, intracellular ATP and F26BP, the substrate of PFKFB3. In Jurkat T cell leukemia cells, PFK15 (3 μM) increased the number of cells undergoing early apoptosis. PFK15 (3 and 20 μM) increased the number of cells undergoing late apoptosis in a dose dependent way [1].

In Lewis lung carcinoma (LLC)-bearing mice, PFK15 inhibited LLC cells metastasized from the subcutaneous to the lungs. PFK15 decreased tumor-associated F26BP and significantly increased the number of cells that were positive for cleaved caspase 3. Also, PFK15 reduced fluoro-D-glucose (18F-FDG) uptake by 50%. PFK15 inhibited the growth of colon and pancreatic adenocarcinomas [1].

Reference:
[1].  Clem BF, O'Neal J, Tapolsky G, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther, 2013, 12(8): 1461-1470.

Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer.[Pubmed:23674815]

Mol Cancer Ther. 2013 Aug;12(8):1461-70.

In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1alpha, and activation of Ras and AKT converge to increase the activity of a key regulator of glycolysis, 6-phosphofructo-2-kinase (PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate (F26BP), which is an activator of 6-phosphofructo-1-kinase, a key step of glycolysis. Previously, a weak competitive inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), was found to reduce the glucose metabolism and proliferation of cancer cells. We have synthesized 73 derivatives of 3PO and screened each compound for activity against recombinant PFKFB3. One small molecule, 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15), was selected for further preclinical evaluation of its pharmacokinetic, antimetabolic, and antineoplastic properties in vitro and in vivo. We found that PFK15 causes a rapid induction of apoptosis in transformed cells, has adequate pharmacokinetic properties, suppresses the glucose uptake and growth of Lewis lung carcinomas in syngeneic mice, and yields antitumor effects in three human xenograft models of cancer in athymic mice that are comparable to U.S. Food and Drug Administration-approved chemotherapeutic agents. As a result of this study, a synthetic derivative and formulation of PFK15 has undergone investigational new drug (IND)-enabling toxicology and safety studies. A phase I clinical trial of its efficacy in advanced cancer patients will initiate in 2013 and we anticipate that this new class of antimetabolic agents will yield acceptable therapeutic indices and prove to be synergistic with agents that disrupt neoplastic signaling.

PFK-015 is an effective inhibitor of PFKFB3 with IC50 of 110 nM (recombinant PFKFB3) and inhibits PFKFB3 activity in cancer cells with IC50 of 20 nM.

PFK-015,4382-63-2,Natural Products, buy PFK-015 , PFK-015 supplier , purchase PFK-015 , PFK-015 cost , PFK-015 manufacturer , order PFK-015 , high purity PFK-015