7K7O

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH COMPOUND-12 AKA:6-[(cyclopropanecarbonyl)amino]-4-{[2-methoxy-3-(pyrimidin-2-yl)phenyl]amino}-N-methylpyridazine-3-carboxamide

Summary for 7K7O

• Entry DOI: 10.2210/pdb7k7o/pdb
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, 6-[(cyclopropanecarbonyl)amino]-4-{[2-methoxy-3-(pyrimidin-2-yl)phenyl]amino}-N-methylpyridazine-3-carboxamide (3 entities in total)
• Functional Keywords: kinase, tyk2, pseudokinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 71837.19

Authors

Khan, J.A. (deposition date: 2020-09-23, release date: 2021-08-04, Last modification date: 2023-10-18)

Primary citation

Liu, C.,Lin, J.,Langevine, C.,Smith, D.,Li, J.,Tokarski, J.S.,Khan, J.,Ruzanov, M.,Strnad, J.,Zupa-Fernandez, A.,Cheng, L.,Gillooly, K.M.,Shuster, D.,Zhang, Y.,Thankappan, A.,McIntyre, K.W.,Chaudhry, C.,Elzinga, P.A.,Chiney, M.,Chimalakonda, A.,Lombardo, L.J.,Macor, J.E.,Carter, P.H.,Burke, J.R.,Weinstein, D.S.
Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2.
J.Med.Chem., 64:677-694, 2021

PubMed Abstract: A search for structurally diversified Tyk2 JH2 ligands from (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the -methyl triazolyl moiety in . The X-ray co-crystal structure of an early lead () revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of . When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of , including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.

PubMed: 33370104
DOI: 10.1021/acs.jmedchem.0c01698

Experimental method

X-RAY DIFFRACTION (2.82 Å)