4GJ2

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

4GJ2 の概要

• エントリーDOI: 10.2210/pdb4gj2/pdb
• 関連するPDBエントリー: 4GI3 4GIH 4GII 4GVJ
• 分子名称: 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)
• 機能のキーワード: kinase, atp binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35116.92

構造登録者

Ultsch, M.H. (登録日: 2012-08-09, 公開日: 2013-05-29, 最終更新日: 2023-09-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.4 Å)