7Q6H
HUMAN JAK3 KINASE DOMAIN WITH 1-(4-((2-((1-methyl-1H-pyrazol-4-yl)amino)quinazolin-8-yl)amino)piperidin-1-yl)ethan-1-one
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Summary for 7Q6H
| Entry DOI | 10.2210/pdb7q6h/pdb |
| Descriptor | Tyrosine-protein kinase JAK3, 1-[4-[[2-[(1-methylpyrazol-4-yl)amino]quinazolin-8-yl]amino]piperidin-1-yl]ethanone, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | inhibitor, jak3, kinase, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37774.99 |
| Authors | Chung, C. (deposition date: 2021-11-07, release date: 2022-02-02, Last modification date: 2024-05-01) |
| Primary citation | Wellaway, C.R.,Baldwin, I.R.,Bamborough, P.,Barker, D.,Bartholomew, M.A.,Chung, C.W.,Dumpelfeld, B.,Evans, J.P.,Fazakerley, N.J.,Homes, P.,Keeling, S.P.,Lewell, X.Q.,McNab, F.W.,Morley, J.,Needham, D.,Neu, M.,van Oosterhout, A.J.M.,Pal, A.,Reinhard, F.B.M.,Rianjongdee, F.,Robertson, C.M.,Rowland, P.,Shah, R.R.,Sherriff, E.B.,Sloan, L.A.,Teague, S.,Thomas, D.A.,Wellaway, N.,Wojno-Picon, J.,Woolven, J.M.,Coe, D.M. Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism. J.Med.Chem., 65:633-664, 2022 Cited by PubMed Abstract: The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung. PubMed: 34928601DOI: 10.1021/acs.jmedchem.1c01765 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.749 Å) |
Structure validation
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