6O8U
Crystal structure of IRAK4 in complex with compound 23
Summary for 6O8U
| Entry DOI | 10.2210/pdb6o8u/pdb |
| Descriptor | Interleukin-1 receptor-associated kinase 4, N-[2,2-dimethyl-6-(morpholin-4-yl)-2,3-dihydro-1-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | kinase, inhibitor, inflammation, lupus, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 139032.26 |
| Authors | Kiefer, J.R.,Yu, C.,Drobnick, J.,Bryan, M.C.,Lupardus, P.J. (deposition date: 2019-03-12, release date: 2019-05-22, Last modification date: 2024-10-30) |
| Primary citation | Bryan, M.C.,Drobnick, J.,Gobbi, A.,Kolesnikov, A.,Chen, Y.,Rajapaksa, N.,Ndubaku, C.,Feng, J.,Chang, W.,Francis, R.,Yu, C.,Choo, E.F.,DeMent, K.,Ran, Y.,An, L.,Emson, C.,Huang, Z.,Sujatha-Bhaskar, S.,Brightbill, H.,DiPasquale, A.,Maher, J.,Wai, J.,McKenzie, B.S.,Lupardus, P.J.,Zarrin, A.A.,Kiefer, J.R. Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors. J.Med.Chem., 62:6223-6240, 2019 Cited by PubMed Abstract: 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. PubMed: 31082230DOI: 10.1021/acs.jmedchem.9b00439 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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