Targeting non-alcoholic fatty liver disease: Design, X-ray co-crystal structure and synthesis of 'first-in-kind' inhibitors of serine/threonine kinase25. (1st November 2022)

• Record Type: Journal Article
• Authors: Kiyeleko, Scarlett; Hocine, Sofiane; Mautino, Giséle; Kuenemann, Mélaine; Nawrotek, Agata; Miallau, Linda; Vuillard, Laurent-Michel; Mirguet, Olivier; Kotschy, Andras; Hanessian, Stephen
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 75(2022)
• Publication Date: 2022-11-01
• Subjects: NAFLD nonalcoholic fatty liver disease -- NASH nonalcoholic steatohepatitis -- STK25 Serine/threonine kinase 25 -- MST3 mammalian sterile20-like kinases 3 -- STK24 Serine/threonine kinase 24 -- YSK1 Yeast Sps1/Ste20-related Kinase 1 -- MO25 Mouse Protein-25 -- B-Raf rapidly accelerated fibrosarcoma B-type -- CDK2 Cyclin-dependent kinase 2 -- FRET Fluorescence Resonance Energy Transfer -- Caco-2 Human Caucasian colon adenocarcinoma -- BA basolateral to apical -- AB apical to basolateral -- HepG2 Hepatoma G2 -- ATP Adenosine Triphosphate -- TBAF Tetra-n-butylammonium fluoride -- DMP Dess–Martin periodinane -- HATU Hexafluorophosphate Azabenztriazole Tetramethyl Uronium -- TBAI Tetra-n-butylammonium iodide -- THF Tetrahydrofuran; Enzyme inhibitor -- Aminopyrazole -- Sulphonamide -- Structure-based design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128950
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We describe the synthesis of a series of 3- t -butyl 5-aminopyrazole p-substituted arylamides as inhibitors of serine-threonine25 (STK25), an enzyme implicated in the progression of non-alcoholic fatty liver disease (NAFLD). Appending a p- N -pyrrolidinosulphonamide group to the arylamide group led to a 'first-in kind' inhibitor with IC50 = 228 nM. A co-crystal structure with STK 25 revealed productive interactions which were also reproduced using molecular docking. A new series of triazolo dihydro oxazine carboxamides of 3- t -butyl 5-aminopyrazole was not active against STK25.