6BBU
Crystal Structure of JAK1 in complex with compound 25
Summary for 6BBU
| Entry DOI | 10.2210/pdb6bbu/pdb |
| Related | 6BBV |
| Descriptor | Tyrosine-protein kinase JAK1, N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (3 entities in total) |
| Functional Keywords | kinase, transferase, 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 | 1 |
| Total formula weight | 36740.88 |
| Authors | |
| Primary citation | Vazquez, M.L.,Kaila, N.,Strohbach, J.W.,Trzupek, J.D.,Brown, M.F.,Flanagan, M.E.,Mitton-Fry, M.J.,Johnson, T.A.,TenBrink, R.E.,Arnold, E.P.,Basak, A.,Heasley, S.E.,Kwon, S.,Langille, J.,Parikh, M.D.,Griffin, S.H.,Casavant, J.M.,Duclos, B.A.,Fenwick, A.E.,Harris, T.M.,Han, S.,Caspers, N.,Dowty, M.E.,Yang, X.,Banker, M.E.,Hegen, M.,Symanowicz, P.T.,Li, L.,Wang, L.,Lin, T.H.,Jussif, J.,Clark, J.D.,Telliez, J.B.,Robinson, R.P.,Unwalla, R. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases. J. Med. Chem., 61:1130-1152, 2018 Cited by PubMed Abstract: Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases. PubMed: 29298069DOI: 10.1021/acs.jmedchem.7b01598 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.08 Å) |
Structure validation
Download full validation report
