4PTE

Structure of a carvoxamide compound (15) (N-[4-(ISOQUINOLIN-7-YL)PYRIDIN-2-YL]CYCLOPROPANECARBOXAMIDE) to GSK3b

Summary for 4PTE

• Entry DOI: 10.2210/pdb4pte/pdb
• Related: 4PTC 4PTG
• Descriptor: Glycogen synthase kinase-3 beta, N-[4-(isoquinolin-7-yl)pyridin-2-yl]cyclopropanecarboxamide (3 entities in total)
• Functional Keywords: serine/threonine kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 2
• Total formula weight: 99168.32

Authors

Lewis, H.A.,Sivaprakasam, P.,Kish, K.,Pokross, M.,Dubowchik, G.M. (deposition date: 2014-03-10, release date: 2015-04-08, Last modification date: 2024-02-28)

Primary citation

Sivaprakasam, P.,Han, X.,Civiello, R.L.,Jacutin-Porte, S.,Kish, K.,Pokross, M.,Lewis, H.A.,Ahmed, N.,Szapiel, N.,Newitt, J.A.,Baldwin, E.T.,Xiao, H.,Krause, C.M.,Park, H.,Nophsker, M.,Lippy, J.S.,Burton, C.R.,Langley, D.R.,Macor, J.E.,Dubowchik, G.M.
Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core.
Bioorg.Med.Chem.Lett., 25:1856-1863, 2015

PubMed Abstract: Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.

PubMed: 25845281
DOI: 10.1016/j.bmcl.2015.03.046

Experimental method

X-RAY DIFFRACTION (2.033 Å)