4E4L
JAK1 kinase (JH1 domain) in complex with compound 30
Summary for 4E4L
| Entry DOI | 10.2210/pdb4e4l/pdb |
| Related | 4E4M 4E4N 4E5W 4E6D 4E6Q |
| Descriptor | Tyrosine-protein kinase JAK1, 1-[4-methyl-1-(methylsulfonyl)piperidin-4-yl]-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (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: P23458 |
| Total number of polymer chains | 4 |
| Total formula weight | 140320.01 |
| Authors | Eigenbrot, C. (deposition date: 2012-03-13, release date: 2012-05-30, Last modification date: 2024-10-30) |
| Primary citation | Kulagowski, J.J.,Blair, W.,Bull, R.J.,Chang, C.,Deshmukh, G.,Dyke, H.J.,Eigenbrot, C.,Ghilardi, N.,Gibbons, P.,Harrison, T.K.,Hewitt, P.R.,Liimatta, M.,Hurley, C.A.,Johnson, A.,Johnson, T.,Kenny, J.R.,Bir Kohli, P.,Maxey, R.J.,Mendonca, R.,Mortara, K.,Murray, J.,Narukulla, R.,Shia, S.,Steffek, M.,Ubhayakar, S.,Ultsch, M.,van Abbema, A.,Ward, S.I.,Waszkowycz, B.,Zak, M. Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors. J.Med.Chem., 55:5901-5921, 2012 Cited by PubMed Abstract: A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity. PubMed: 22591402DOI: 10.1021/jm300438j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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