6o95

Structure of the IRAK4 kinase domain with compound 41

spinqualitylabelsall models 6o95, resolution 1.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6o95 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.77Å Ligands: LSV, SEP, SO4, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model. Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.,Bryan MC, Drobnick J, Gobbi A, Kolesnikov A, Chen Y, Rajapaksa N, Ndubaku C, Feng J, Chang W, Francis R, Yu C, Choo EF, DeMent K, Ran Y, An L, Emson C, Huang Z, Sujatha-Bhaskar S, Brightbill H, DiPasquale A, Maher J, Wai J, McKenzie BS, Lupardus PJ, Zarrin AA, Kiefer JR J Med Chem. 2019 May 24. doi: 10.1021/acs.jmedchem.9b00439. PMID:31082230 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Interleukin-1 receptor-associated kinase

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