5WAL
Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model
Summary for 5WAL
Entry DOI | 10.2210/pdb5wal/pdb |
Descriptor | Non-receptor tyrosine-protein kinase TYK2, N-[2-(2,6-dichlorophenyl)-1H-imidazo[4,5-c]pyridin-4-yl]cyclopropanecarboxamide (3 entities in total) |
Functional Keywords | tyk2, kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 1 |
Total formula weight | 35095.93 |
Authors | Ultsch, M.H.,Magnuson, S. (deposition date: 2017-06-26, release date: 2017-09-06, Last modification date: 2023-10-04) |
Primary citation | Liang, J.,Van Abbema, A.,Balazs, M.,Barrett, K.,Berezhkovsky, L.,Blair, W.S.,Chang, C.,Delarosa, D.,DeVoss, J.,Driscoll, J.,Eigenbrot, C.,Goodacre, S.,Ghilardi, N.,MacLeod, C.,Johnson, A.,Bir Kohli, P.,Lai, Y.,Lin, Z.,Mantik, P.,Menghrajani, K.,Nguyen, H.,Peng, I.,Sambrone, A.,Shia, S.,Smith, J.,Sohn, S.,Tsui, V.,Ultsch, M.,Williams, K.,Wu, L.C.,Yang, W.,Zhang, B.,Magnuson, S. Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model. Bioorg. Med. Chem. Lett., 27:4370-4376, 2017 Cited by PubMed Abstract: Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients. PubMed: 28830649DOI: 10.1016/j.bmcl.2017.08.022 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.45 Å) |
Structure validation
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