7SXF

BIO-2895 (BRD0705) bound GSK3alpha-axin complex

Summary for 7SXF

• Entry DOI: 10.2210/pdb7sxf/pdb
• Descriptor: Glycogen synthase kinase-3 alpha, Axin peptide, (4~{S})-4-ethyl-7,7-dimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one, ... (5 entities in total)
• Functional Keywords: kinase, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 41663.10

Authors

Chodaparambil, J.V. (deposition date: 2021-11-23, release date: 2023-06-14, Last modification date: 2024-11-06)

Primary citation

Amaral, B.,Capacci, A.,Anderson, T.,Tezer, C.,Bajrami, B.,Lulla, M.,Lucas, B.,Chodaparambil, J.V.,Marcotte, D.,Kumar, P.R.,Murugan, P.,Spilker, K.,Cullivan, M.,Wang, T.,Peterson, A.C.,Enyedy, I.,Ma, B.,Chen, T.,Yousaf, Z.,Calhoun, M.,Golonzhka, O.,Dillon, G.M.,Koirala, S.
Elucidation of the GSK3 alpha Structure Informs the Design of Novel, Paralog-Selective Inhibitors.
Acs Chem Neurosci, 14:1080-1094, 2023

PubMed Abstract: Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/β-catenin pathway and potential for aberrant cell proliferation. Development of GSK3α or GSK3β paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3α. Here we report for the first time the crystal structure for GSK3α, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel compounds with up to ∼37-fold selectivity for GSK3α over GSK3β with favorable drug-like properties. Furthermore, using chemoproteomics, we confirm that acute inhibition of GSK3α can lower tau phosphorylation at disease-relevant sites in vivo, with a high degree of selectivity over GSK3β and other kinases. Altogether, our studies advance prior efforts to develop GSK3 inhibitors by describing GSK3α structure and novel GSK3α inhibitors with improved selectivity, potency, and activity in disease-relevant systems.

PubMed: 36812145
DOI: 10.1021/acschemneuro.2c00476

Experimental method

X-RAY DIFFRACTION (1.94 Å)