4ACG

GSK3b in complex with inhibitor

Summary for 4ACG

• Entry DOI: 10.2210/pdb4acg/pdb
• Related: 1GNG 1H8F 1I09 1J1B 1J1C 1O6K 1O6L 1O9U 1PYX 1Q3D 1Q3W 1Q41 1Q4L 1Q5K 1R0E 1UV5 2JDO 2JDR 2JLD 2UW9 2X37 2X39 2XH5 3ZRK 3ZRL 3ZRM 4ACC 4ACD 4ACH
• Descriptor: GLYCOGEN SYNTHASE KINASE-3 BETA, 2-AMINO-5-{4-[(4-METHYLPIPERAZIN-1-YL)SULFONYL]PHENYL}-N-[4-(PYRROLIDIN-1-YLMETHYL)PYRIDIN-3-YL]PYRIDINE-3-CARBOXAMIDE (3 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : P49841
• Total number of polymer chains: 2
• Total formula weight: 105221.06

Authors

Xue, Y.,Ormo, M. (deposition date: 2011-12-15, release date: 2012-05-16, Last modification date: 2024-05-08)

Primary citation

Berg, S.,Bergh, M.,Hellberg, S.,Hogdin, K.,Lo-Alfredsson, Y.,Soderman, P.,von Berg, S.,Weigelt, T.,Ormo, M.,Xue, Y.,Tucker, J.,Neelissen, J.,Jerning, E.,Nilsson, Y.,Bhat, R.
Discovery of novel potent and highly selective glycogen synthase kinase-3 beta (GSK3 beta ) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines.
J. Med. Chem., 55:9107-9119, 2012

PubMed Abstract: Glycogen synthase kinase-3β, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3β localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.

PubMed: 22489897
DOI: 10.1021/jm201724m

Experimental method

X-RAY DIFFRACTION (2.6 Å)