TEPP46 [ML-265] (CAS: 1221186-53-3)

C₁₇H₁₆N₄O₂S₂

• Potent and selective cell permeable pyruvate kinase M2 (PKM2) activator with little or no activity versus PKM1, PKL and PKR.
• Useful agent for immunometabolism research.
• Anticancer (reducing tumor sizes in mice) and anti-inflammatory agent.
• Shown to bind the enzyme PKM2 to promote formation of stable, enzymatically-active tetramers, thereby promoting the last rate-limiting step of glycolysis, converting PEP to pyruvate. In addition, it prevents PKM2 translocation to the nucleus resulting in reduced glycolysis and HIF-1α activation, causing diminished Warburg effect and IL-1β production.

1. J.K. Jiang et al. Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase: J.K. Jiang, et al.; Bioorg. Med. Chem. Lett. 20, 3387 (2010)
2. ML265: A potent PKM2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft model: M.J. Walsh, et al.; Probe Rep. NIH Mol. Libr. Prog. (2012)
3. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis: D. Anastasiou, et al.; Nat. Chem. Biol. 8, 839 (2012)
4. Pyruvate Kinase M2 regulates HIF-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages: E.M. Palsson-McDermott, et al.; Cell Metab. 21, 65 (2015)
5. A guide to immunometabolism for immunologists: L.A. O'Neill, et al.; Nat. Rev. Immunol. 16, 553 (2016)
6. Pyruvate Kinase M2: A Potential Target for Regulating Inflammation: J.C. Alves-Filho & E.M. Palsson-McDermott; Front. Immunol. 7, 145 (2016) (Review)
7. Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors: G. Andrejeva & J.C. Rathmell; Cell Metab. 26, 49 (2017)
8. Targeting metabolism as a novel therapeutic approach to autoimmunity, inflammation and transplantation: I.A. Bettencourt & J.D. Powell; J. Immunol. 198, 999 (2017)
9. Caloric Restriction Mimetic 2-Deoxyglucose Alleviated Inflammatory Lung Injury via Suppressing Nuclear Pyruvate Kinase M2-Signal Transducer and Activator of Transcription 3 Pathway: K. Hu, et al.; Front. Immunol. 9, 426 (2018)