4y8d
Crystal structure of Cyclin-G associated kinase (GAK) complexed with selective 12i inhibitorCrystal structure of Cyclin-G associated kinase (GAK) complexed with selective 12i inhibitor
Structural highlights
FunctionGAK_HUMAN Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.[1] Publication Abstract from PubMedCyclin-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). Selective inhibitors of Cyclin-G associated kinase (GAK) as anti-HCV agents.,Kovackova S, Chang L, Bekerman E, Neveu G, Barouch-Bentov R, Chaikuad A, Heroven C, Sala M, De Jonghe SC, Knapp S, Einav S, Herdewijn P J Med Chem. 2015 Mar 30. PMID:25822739[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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