4GIH

Tyk2 (JH1) in complex with 2,6-DICHLORO-N-{2-[(CYCLOPROPYLCARBONYL)AMINO]PYRIDIN-4-YL}BENZAMIDE

4GIH の概要

• エントリーDOI: 10.2210/pdb4gih/pdb
• 関連するPDBエントリー: 4GFM 4GFO 4GII 4GJ2 4GJ3 4GMY 4GVJ
• 分子名称: Non-receptor tyrosine-protein kinase TYK2, 2,6-dichloro-N-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}benzamide (3 entities in total)
• 機能のキーワード: tyrosine kinase, kinase, atp binding, inhibitor, 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: 35098.93

構造登録者

Ultsch, M.H. (登録日: 2012-08-08, 公開日: 2013-06-19, 最終更新日: 2023-09-13)

主引用文献

Liang, J.,Tsui, V.,Van Abbema, A.,Bao, L.,Barrett, K.,Beresini, M.,Berezhkovskiy, L.,Blair, W.S.,Chang, C.,Driscoll, J.,Eigenbrot, C.,Ghilardi, N.,Gibbons, P.,Halladay, J.,Johnson, A.,Kohli, P.B.,Lai, Y.,Liimatta, M.,Mantik, P.,Menghrajani, K.,Murray, J.,Sambrone, A.,Xiao, Y.,Shia, S.,Shin, Y.,Smith, J.,Sohn, S.,Stanley, M.,Ultsch, M.,Zhang, B.,Wu, L.C.,Magnuson, S.
Lead identification of novel and selective TYK2 inhibitors.
Eur.J.Med.Chem., 67:175-187, 2013

PubMed Abstract: A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.

PubMed: 23867602
DOI: 10.1016/j.ejmech.2013.03.070

実験手法

X-RAY DIFFRACTION (2 Å)