Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors

• Published in: Organic & biomolecular chemistry 2024-09, Vol.22 (36), p.7373-7389
• Main Authors: Ivanova, Yulia, Spittaels, Sander, Gao, Ling-Jie, Schols, Dominique, Van Meervelt, Luc, Froeyen, Mathy, Dehaen, Wim, De Jonghe, Steven
• Format: Article
• Language: English
• Subjects: Binders; Chemical synthesis; Cyclin G; Enzyme inhibitors; Humans; Inhibitors; Intracellular Signaling Peptides and Proteins; Kinases; Models, Molecular; Molecular modelling; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Pyridines; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d4ob00908h

Isothiazolo[4,3- b ]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5- b ]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5- b ]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5- b ]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders. A novel route to various substituted isothiazolo[4,5- b ]pyridines was established. The compounds completely lacked GAK affinity, which was explained by in silico analysis.