4GFM

JAK2 kinase (JH1 domain) with 2,6-DICHLORO-N-(2-OXO-2,5-DIHYDROPYRIDIN-4-YL)BENZAMIDE

Summary for 4GFM

• Entry DOI: 10.2210/pdb4gfm/pdb
• Related: 4GFO 4GIH 4GMY
• Descriptor: Tyrosine-protein kinase JAK2, 2,6-dichloro-N-(2-oxo-2,5-dihydropyridin-4-yl)benzamide (3 entities in total)
• Functional Keywords: o-phosphotyrosine, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system; Peripheral membrane protein (By similarity): O60674
• Total number of polymer chains: 1
• Total formula weight: 35769.36

Authors

Eigenbrot, C.,Ultsch, M. (deposition date: 2012-08-03, release date: 2013-06-19, Last modification date: 2024-10-16)

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 (2.3 Å)