European Journal of Medicinal Chemistry, 15:250:115177 (2023)
DOI: 10.1016/j.ejmech.2023.115177
Pubmed: 36753880
PDB coordinates:
7FRW (3D view ), 7FRV (3D view ), 7FRX (3D view ), 7FRZ (3D view ), 7FS0 (3D view ), 7FS1 (3D view ), 7FS2 (3D view ), 7FS3 (3D view ), 7FS4 (3D view ), 7FS5 (3D view ), 7FS6 (3D view ), 7FS7 (3D view ), 7FS8 (3D view ), 7FS9 (3D view ), 7FSA (3D view ), 7FSB (3D view ), 7FSC (3D view ), 7FSD (3D view )
Abstract
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. Continue reading →
