8DJC

CRYSTAL STRUCTURE OF GLYCOGEN SYNTHASE KINASE 3 BETA COMPLEXED WITH (4S)-N-{4-[(2S)-2-methylmorpholin-4-yl] pyridin-3-yl}-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide

Summary for 8DJC

• Entry DOI: 10.2210/pdb8djc/pdb
• Descriptor: Glycogen synthase kinase-3 beta, (4S)-N-{4-[(2S)-2-methylmorpholin-4-yl]pyridin-3-yl}-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide (3 entities in total)
• Functional Keywords: kinase, gsk3b, transferase-transferase inhibitor complex, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 99418.58

Authors

Lewis, H.A.,Muckelbauer, J.K. (deposition date: 2022-06-30, release date: 2023-03-22, Last modification date: 2024-04-03)

Primary citation

Hartz, R.A.,Ahuja, V.T.,Sivaprakasam, P.,Xiao, H.,Krause, C.M.,Clarke, W.J.,Kish, K.,Lewis, H.,Szapiel, N.,Ravirala, R.,Mutalik, S.,Nakmode, D.,Shah, D.,Burton, C.R.,Macor, J.E.,Dubowchik, G.M.
Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2- b ]pyridazines as Glycogen Synthase Kinase-3 beta (GSK-3 beta ) Inhibitors.
J.Med.Chem., 66:4231-4252, 2023

PubMed Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3β has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo[1,2-]pyridazine derivatives that were evaluated as GSK-3β inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3β inhibitors. In vivo studies with in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3β inhibitor that significantly lowered levels of phosphorylated tau.

PubMed: 36950863
DOI: 10.1021/acs.jmedchem.3c00133

Experimental method

X-RAY DIFFRACTION (2.463 Å)