ml-265

Description: TEPP-46 HCl (ML-265) is a novel potent and selective small molecule activator of pyruvatekinase M2 (PKM2) with an EC50 of 92 nM, it showed little or no effect onPKM1, PKL and PKR. Macrophages activated by the TLR4 agonist LPSundergo dramatic changes in their metabolic activity. LPS inducesexpression 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 theexpression of a range of other Hif-1alpha-dependent genes. Activation ofPKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotypewhile promoting traits typical of an M2 macrophage. LPS-induced PKM2enters into a complex with Hif-1alpha, which can directly bind to the IL-1betapromoter, an event that is inhibited by activation of PKM2. TEPP-46inhibited LPS-induced glycolytic reprogramming and succinate production.Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS andSalmonella typhimurium-induced IL-1beta production, while boostingproduction of IL-10. PKM2 is therefore a critical determinant ofmacrophage 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.