4Y8D

Crystal structure of Cyclin-G associated kinase (GAK) complexed with selective 12i inhibitor

Summary for 4Y8D

• Entry DOI: 10.2210/pdb4y8d/pdb
• Descriptor: Cyclin-G-associated kinase, nanobody, 2-methoxy-4-[3-(morpholin-4-yl)[1,2]thiazolo[4,3-b]pyridin-6-yl]aniline, ... (5 entities in total)
• Functional Keywords: transferase, kinase, nanobody, inhibitor, structural genomics, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm, perinuclear region : O14976
• Total number of polymer chains: 4
• Total formula weight: 107533.29

Authors

Chaikuad, A.,Heroven, C.,Nowak, R.,De Jonghe, S.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2015-02-16, release date: 2015-04-08, Last modification date: 2024-10-09)

Primary citation

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.
Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents.
J.Med.Chem., 58:3393-3410, 2015

PubMed 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. Cocrystallization 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 life cycle (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).

PubMed: 25822739
DOI: 10.1021/jm501759m

Experimental method

X-RAY DIFFRACTION (2.1 Å)