Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators

• Published in: European journal of medicinal chemistry Vol. 250; p. 115177
• Main Authors: Nain-Perez, Amalyn, Nilsson, Oscar, Lulla, Aleksei, Håversen, Liliana, Brear, Paul, Liljenberg, Sara, Hyvönen, Marko, Borén, Jan, Grøtli, Morten
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.03.2023; Elsevier
• Subjects: Activation; activators; Cell Line; Chemistry, Medicinal; Enzyme activity; Farmakologi och toxikologi; Hepatocytes - metabolism; Inhibition; Life Sciences & Biomedicine; Lipogenesis; Liver - metabolism; m2 isoform; Modulation; Pharmacology & Pharmacy; Pharmacology and Toxicology; PKL; Pyruvate kinase; Pyruvate Kinase - metabolism; Science & Technology; site; PKL; Activation; Enzyme activity; Inhibition; Pyruvate kinase; Modulation; SITE; M2 ISOFORM; ACTIVATORS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115177

The liver isoform of pyruvate kinase (PKL) has gained interest due to its potential capacity to regulate fatty acid synthesis involved in the progression of non-alcoholic fatty liver disease (NAFLD). Here we describe a novel series of PKL modulators that can either activate or inhibit the enzyme allosterically, from a cryptic site at the interface of two protomers in the tetrameric enzyme. Starting from urolithin D, we designed and synthesised 42 new compounds. The effect of these compounds on PKL enzymatic activity was assessed after incubation with cell lysates obtained from a liver cell line. Pronounced activation of PKL activity, up to 3.8-fold, was observed for several compounds at 10 μM, while other compounds were prominent PKL inhibitors reducing its activity to 81% at best. A structure-activity relationship identified linear-shaped sulfone-sulfonamides as activators and non-linear compounds as inhibitors. Crystal structures revealed the conformations of these modulators, which were used as a reference for designing new modulators. [Display omitted] •Allosteric modulators of liver pyruvate kinase (PKL) were designed and synthesised.•The best PKL inhibitor showed 81% inhibition of PKL cell lysate.•The best PKL activator showed 380% activation of PKL cell lysate.•Both inhibitors and activators bind in the same allosteric binding pocket.•Targeting PKL allosterically can result in up or down-regulation.