Background:

ML-265 (TEPP-46) is a potent and selective PKM2 activator [1][2].

Pyruvate kinase catalyzes the final step in glycolysis and transfers the phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP) to yield adenosine triphosphate (ATP) and pyruvate. Pyruvate kinase M2 (PKM2) is considerably less active and expressed in highly proliferative cells including all cancer cell lines and tumors, which require high amounts of glucose for proliferation [1][2].

ML-265 is a potent and selective PKM2 activator with AC50 value of 92 nM. ML-265 exhibits high selectivity over PKM1, PKR and PKL. ML-265 decreased the Km of PKM2 for PEP in a way similar to the endogenous activator FBP. ML-265 also increased PKM2 activity by promoting the tetrameric state [1].

In mice with A549 xenograft tumors, ML-265 exhibited good oral bioavailability with relatively low clearance, long half-life. ML-265 (150 mg/kg) readily achieved maximal PKM2 activation. In mice bearing H1299 xenograft tumors, ML-265 inhibited tumor growth, suggesting that increased pyruvate kinase activity can impair tumorigenesis [1][2].

参考文献:
[1].  Anastasiou D, Yu Y, Israelsen WJ, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012 Oct;8(10):839-47.
[2].  Walsh MJ, Brimacombe KR, Anastasiou D, et al. ML265: A potent PKM2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft model. Probe Reports from the NIH Molecular Libraries Program [Internet].