4GJ2

Tyk2 (JH1) in complex with 2,6-dichloro-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide

Summary for 4GJ2

• Entry DOI: 10.2210/pdb4gj2/pdb
• Related: 4GI3 4GIH 4GII 4GVJ
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, 2,6-dichloro-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide (3 entities in total)
• Functional Keywords: kinase, atp binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35116.92

Authors

Ultsch, M.H. (deposition date: 2012-08-09, release date: 2013-05-29, Last modification date: 2023-09-13)

Primary citation

Liang, J.,van Abbema, A.,Balazs, M.,Barrett, K.,Berezhkovsky, L.,Blair, W.,Chang, C.,Delarosa, D.,Devoss, J.,Driscoll, J.,Eigenbrot, C.,Ghilardi, N.,Gibbons, P.,Halladay, J.,Johnson, A.,Kohli, P.B.,Lai, Y.,Liu, Y.,Lyssikatos, J.,Mantik, P.,Menghrajani, K.,Murray, J.,Peng, I.,Sambrone, A.,Shia, S.,Shin, Y.,Smith, J.,Sohn, S.,Tsui, V.,Ultsch, M.,Wu, L.C.,Xiao, Y.,Yang, W.,Young, J.,Zhang, B.,Zhu, B.Y.,Magnuson, S.
Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors.
J.Med.Chem., 56:4521-4536, 2013

PubMed Abstract: Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.

PubMed: 23668484
DOI: 10.1021/jm400266t

Experimental method

X-RAY DIFFRACTION (2.4 Å)