Friday, April 24, 2015

Drugs in Clinical Pipeline: PFK-015

PFK-015 [(E)-3-(pyridin-3-yl)-1-(quinolin-3-yl)prop-2-en-1-one], is a potent inhibitor of 6-Phosphofructo-2-kinase/Fructose-2,6-biphosphatase 3 (PFKFB3), and preliminary results in a U87GM xenograft model have shown that PFK-015 has comparable activity to Temozolomide and that PFK-015 crosses the blood brain barrier.

The activity of PFK-015 is as follows:

IC50 (PFKFB3 enzyme assay) = 318 ± 19 nM
IC50 (PFKFB3 enzymatic activity in cells) = 4.7 ± 1.6 uM
IC50 (Inhibition of deoxyglucose uptake) = 1.2 ± 0.1 uM
IC50 (Toxicity of Jurkat) = 0.8 ± 0.1 uM

Common Name: PFK-015
Synonyms:  PFK-015; PFK 015; PFK015
IUPAC Name: (E)-3-(pyridin-3-yl)-1-(quinolin-3-yl)prop-2-en-1-one
CAS Number: 4382-63-2
Mechanism of Action: Kinase Inhibitor; PFKFB3 Inhibitor
Indication: Various Cancers; Glioblastomas
Development Stage: Investigational
Company: Advanced Cancer Therapeutics

The glycolytic pathway is a ten-step series of reactions that forms the major metabolic pathway in nearly all organisms. Flux through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. Irreversible glycolytic reactions are those catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase. In metabolic pathways, such enzymes are potential targets for control, and all three enzymes serve this purpose in glycolysis. The PFKFB enzymes (PFKFB 1-4) synthesize fructose-2,6-bisphosphate (F2,6BP) which activates 6-phosphofructo-1- kinase (PFK-1), an essential control point in the glycolytic pathway. Neoplastic cells preferentially utilize glycolysis to satisfy their increased needs for energy and biosynthetic precursors. Malignant tumor cells have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin. One cancer attack strategy has been to treat cancer by starving cancerous cells in various ways. Reducing or blocking the enhanced glycolytic flux mechanism present in cancer cells has stimulated recent interest.

Over-expression of HIF-1a, activation of Ras and loss of p53 tumor suppressor function are associated with the development of human cancers and each of these genetic alterations converge on glycolysis by activating the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB). The PFKFB enzymes interconvert fructose-6-phosphate (F6P) and fructose-2,6-bisphosphate (F2,6BP) and F2,6BP is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and control point in the glycolytic pathway. There are four PFKFB family members which are encoded by separate genes (PFKFB1-4) and characterized by distinct kinase:bisphosphatase ratios. The PFKFB3 family member is of particular interest since it has been found to be activated in human cancer cell lines and tumors, to be increased by hypoxic exposure via HIF-1a and by oncogenic Ras, and to be required for tumorigenic growth [1].

Advanced Cancer Therapeutics (ACT) is developing inhibitors of glycolysis targeting 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a cancer metabolism target identified as essential for cancer cell growth and licensed by ACT from the James Graham Brown Cancer Center. High glucose consumption is observed in most cancers. PFKFB3 is the enzyme involved in the first irreversible step of glycolysis, and has been validated as a relevant cancer metabolism target. Inhibitors of the PFKFB3 block glucose uptake and inhibit tumor growth.

Preliminary results obtained with PFK-015, in a glioblastoma xenograft model have shown that it has tumor growth inhibition activity comparable to that of Temozolomide, the drug currently used as first line therapy for the treatment of glioblastoma multiforme. Furthermore, PFK-015 inhibits glucoseuptake by tumors as shown by PET imaging and crosses the blood brain barrier [1].

1. Clem, B.; et. al. Abstract 2825: Characterization of a novel small molecule antagonist of 6-phosphofructo-2-kinase that suppresses glucose metabolism and tumor growth. Cancer Res 2011, 71, 2825.
2. Chesney, J.; et. al. PFKB3 inhibitor for the treatment of a proliferative cancer. US8088385B2