6NSL

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound-6c AKA 6-((1-(4-CYANOPHENY L)-2-OXO-1,2-DIHYDRO-3-PYRIDINYL)AMINO)-N-CYCLOPROPYL-8-(M ETHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBOXAMIDE

Summary for 6NSL

• Entry DOI: 10.2210/pdb6nsl/pdb
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, 6-{[1-(4-cyanophenyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}-N-cyclopropyl-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72167.42

Authors

Muckelbauer, J.M.,Khan, J.A. (deposition date: 2019-01-25, release date: 2020-01-29, Last modification date: 2024-03-13)

Primary citation

Liu, C.,Lin, J.,Moslin, R.,Tokarski, J.S.,Muckelbauer, J.,Chang, C.,Tredup, J.,Xie, D.,Park, H.,Li, P.,Wu, D.R.,Strnad, J.,Zupa-Fernandez, A.,Cheng, L.,Chaudhry, C.,Chen, J.,Chen, C.,Sun, H.,Elzinga, P.,D'arienzo, C.,Gillooly, K.,Taylor, T.L.,McIntyre, K.W.,Salter-Cid, L.,Lombardo, L.J.,Carter, P.H.,Aranibar, N.,Burke, J.R.,Weinstein, D.S.
Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors.
Acs Med.Chem.Lett., 10:383-388, 2019

PubMed Abstract: In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor , which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

PubMed: 30891145
DOI: 10.1021/acsmedchemlett.9b00035

Experimental method

X-RAY DIFFRACTION (2.15 Å)