6H0U

Glycogen synthase kinase-3 beta (GSK3) complex with a covalent [1,2,4]triazolo[1,5-a][1,3,5]triazine inhibitor

Summary for 6H0U

• Entry DOI: 10.2210/pdb6h0u/pdb
• Descriptor: Glycogen synthase kinase-3 beta, (2~{R})-3-[7-azanyl-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl]-2-cyano-propanamide, MALONATE ION, ... (7 entities in total)
• Functional Keywords: protein kinase, gsk3beta-covalent inhibitor complex, parkinson disease, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 94733.37

Authors

Marcovich, I.,Demitri, N.,De Zorzi, R.,Storici, P. (deposition date: 2018-07-10, release date: 2019-05-15, Last modification date: 2024-01-17)

Primary citation

Redenti, S.,Marcovich, I.,De Vita, T.,Perez, C.,De Zorzi, R.,Demitri, N.,Perez, D.I.,Bottegoni, G.,Bisignano, P.,Bissaro, M.,Moro, S.,Martinez, A.,Storici, P.,Spalluto, G.,Cavalli, A.,Federico, S.
A Triazolotriazine-Based Dual GSK-3 beta /CK-1 delta Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition.
Chemmedchem, 14:310-314, 2019

PubMed Abstract: Glycogen synthase kinase 3β (GSK-3β) and casein kinase 1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3β and CK-1δ [IC (GSK-3β)=0.17 μm; IC (CK-1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3β/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.

PubMed: 30548443
DOI: 10.1002/cmdc.201800778

Experimental method

X-RAY DIFFRACTION (2.3 Å)