Structure‐Based Design of Small‐Molecule Ligands of Phosphofructokinase‐2 Activating or Inhibiting Glycolysis

Abstract

Glycolysis lies at the basis of metabolism and cell energy supply. The disregulation of glycolysis is involved in such pathological processes as cancer proliferation, neurodegenerative diseases, and amplification of ischemic damage. Phosphofructokinase-2 (PFK-2), a bifunctional enzyme and regulator of glycolytic flux, has recently emerged as a promising anticancer target. Herein, the computer-aided design of a new class of aminofurazan-triazole regulators of PFK-2 is described along with the results of their in vitro evaluation. The aminofurazan-triazoles differ from other recently described inhibitors of PFK-2 and demonstrate the ability to modulate glycolytic flux in rat muscle lysate, producing a twofold decrease by inhibitors and fourfold increase by activators. The most potent compounds in the series were shown to inhibit the kinase activity of the hypoxia-inducible form of PFK-2, PFKFB3, as well as proliferation of HeLa, lung adenocarcinoma, colon adenocarcinoma, and breast cancer cells at concentrations in the low micromolar range.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-1,2,5-oxadiazol-3-amine

“…1,2,5-Oxadiazoles containing a pyrrole group at position 3 are known to exhibit antiproliferative activity in the sea urchin embryo model and in cultured human cancer cell lines [10,11]. In addition, many 1,2,5-oxadiazole-3-amines with a heterocyclic substituent at position 4 are known to have valuable pharmacological activity, see, for example, references [12][13][14][15][16]. Therefore, compound 5 may also have useful pharmacological properties.…”

Furazans in Medicinal Chemistry

“…Patents from 4SC disclosed a series of furazanopyrazines which inhibit multiple kinases and growth factors involved in cancer cell survival, proliferation, migration and metastasis 238 (87); targeting multiple aspects of tumorigenesis ("multiplex protein kinase inhibition") could enable broad spectrum anticancer activity. Furazanyl triazoles identified by Pyrkov et al inhibit phosphofructokinase, having antiproliferative effects against lung, colon and breast cancer cell lines 239 (88). More information regarding the development of these inhibitors or their efficacy as a cancer treatment has not been reported, nor are they listed in company pipelines.…”

An update on therapeutic opportunities offered by cancer glycolytic metabolism

“…39 Compound 20 in Figure 3 is the most potent PFKFB3 inhibitor of this series, by reducing the PFKFB activity in enzymatic assays (although complete inhibition was not reached even at the highest tested concentration of 100 lM) and by decreasing the glycolytic flux in rat muscle cell lysates at the concentration of 3 lM.…”