7q7w

JAK2 in complex with 4-(2-{[5-(dimethylamino)pentyl]amino}-8-{[(2S)-1-hydroxypropan-2-yl]amino}quinazolin-6-yl)-5-ethyl-2-fluorophenol

spinqualitylabelsall models 7q7w, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: 9HR, PTR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.,Wellaway CR, Baldwin IR, Bamborough P, Barker D, Bartholomew MA, Chung CW, Dumpelfeld B, Evans JP, Fazakerley NJ, Homes P, Keeling SP, Lewell XQ, McNab FW, Morley J, Needham D, Neu M, van Oosterhout AJM, Pal A, Reinhard FBM, Rianjongdee F, Robertson CM, Rowland P, Shah RR, Sherriff EB, Sloan LA, Teague S, Thomas DA, Wellaway N, Wojno-Picon J, Woolven JM, Coe DM J Med Chem. 2022 Jan 13;65(1):633-664. doi: 10.1021/acs.jmedchem.1c01765. Epub, 2021 Dec 20. PMID:34928601 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Janus kinase 3D structures

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