5K5N

Crystal structure of GSK-3beta complexed with PF-04802367, a highly selective brain-penetrant kinase inhibitor

Summary for 5K5N

• Entry DOI: 10.2210/pdb5k5n/pdb
• Descriptor: Glycogen synthase kinase-3 beta, 5-(3-chloranyl-4-methoxy-phenyl)-~{N}-[3-(1,2,4-triazol-1-yl)propyl]-1,3-oxazole-4-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: protein kinase, alzhimer's disease, tau kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 2
• Total formula weight: 85170.04

Authors

Kurumbail, R.G.,Chang, J.S. (deposition date: 2016-05-23, release date: 2016-09-21)

Primary citation

Liang, S.H.,Chen, J.M.,Normandin, M.D.,Chang, J.S.,Chang, G.C.,Taylor, C.K.,Trapa, P.,Plummer, M.S.,Para, K.S.,Conn, E.L.,Lopresti-Morrow, L.,Lanyon, L.F.,Cook, J.M.,Richter, K.E.,Nolan, C.E.,Schachter, J.B.,Janat, F.,Che, Y.,Shanmugasundaram, V.,Lefker, B.A.,Enerson, B.E.,Livni, E.,Wang, L.,Guehl, N.J.,Patnaik, D.,Wagner, F.F.,Perlis, R.,Holson, E.B.,Haggarty, S.J.,El Fakhri, G.,Kurumbail, R.G.,Vasdev, N.
Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.
Angew.Chem.Int.Ed.Engl., 55:9601-9605, 2016

PubMed Abstract: Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.

PubMed: 27355874
DOI: 10.1002/anie.201603797

Experimental method

X-RAY DIFFRACTION (2.2 Å)