4GIH

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

Summary for 4GIH

• Entry DOI: 10.2210/pdb4gih/pdb
• Related: 4GFM 4GFO 4GII 4GJ2 4GJ3 4GMY 4GVJ
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, 2,6-dichloro-N-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}benzamide (3 entities in total)
• Functional Keywords: tyrosine kinase, kinase, atp binding, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35098.93

Authors

Ultsch, M.H. (deposition date: 2012-08-08, release date: 2013-06-19, Last modification date: 2023-09-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)