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Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents JOURNAL OF MEDICINAL CHEMISTRY Kovackova, S., Chang, L., Bekerman, E., Neveu, G., Barouch-Bentov, R., Chaikuad, A., Heroven, C., Sala, M., De Jonghe, S., Knapp, S., Einav, S., Herdewijn, P. 2015; 58 (8): 3393-3410

Abstract

Cyclin-G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Co-crystallization experiments revealed that these compounds behaved as classic type I ATP-competitive kinase inhibitors. In addition, we have demonstrated that these compounds exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV lifecycle (i.e. viral entry and assembly). Hence, these GAK inhibitors represent chemical probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer and Parkinson's disease).

View details for DOI 10.1021/jm501759m

View details for Web of Science ID 000353602200009

View details for PubMedID 25822739