5F95

Crystal structure of GSK3b in complex with Compound 18: 2-[(cyclopropylcarbonyl)amino]-N-(4-phenylpyridin-3-yl)pyridine-4-carboxamide

Summary for 5F95

• Entry DOI: 10.2210/pdb5f95/pdb
• Related: 5F94
• Descriptor: Glycogen synthase kinase-3 beta, 2-[(cyclopropylcarbonyl)amino]-N-(4-phenylpyridin-3-yl)pyridine-4-carboxamide (3 entities in total)
• Functional Keywords: gsk3b, 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: 80404.48

Authors

Lewis, H.A.,Kish, K.,Luo, G.,Dubowchick, G.M. (deposition date: 2015-12-09, release date: 2016-02-03, Last modification date: 2024-03-06)

Primary citation

Luo, G.,Chen, L.,Burton, C.R.,Xiao, H.,Sivaprakasam, P.,Krause, C.M.,Cao, Y.,Liu, N.,Lippy, J.,Clarke, W.J.,Snow, K.,Raybon, J.,Arora, V.,Pokross, M.,Kish, K.,Lewis, H.A.,Langley, D.R.,Macor, J.E.,Dubowchik, G.M.
Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors.
J.Med.Chem., 59:1041-1051, 2016

PubMed Abstract: GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.

PubMed: 26751161
DOI: 10.1021/acs.jmedchem.5b01550

Experimental method

X-RAY DIFFRACTION (2.525 Å)