TEPP-46 (ML-265)

Description: TEPP-46 is a novel potent and selective small molecule activator of pyruvate kinase M2 (PKM2) with an EC50 of 92 nM, it showed little or no effect on PKM1, PKL and PKR. Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using the well-characterized small molecules, TEPP-46, inhibited LPS-induced Hif-1alpha and IL-1beta, as well as the expression of a range of other Hif-1alpha-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. LPS-induced PKM2 enters into a complex with Hif-1alpha, which can directly bind to the IL-1beta promoter, an event that is inhibited by activation of PKM2. TEPP-46 inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1beta production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

References: Cell Metab. 2015 Jan 6; 21(1):65-80; Nat Chem Biol. 2012 Oct; 8(10):839-47.