6O94

Structure of the IRAK4 kinase domain with compound 17

Summary for 6O94

• Entry DOI: 10.2210/pdb6o94/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, CALCIUM ION, N-{5-[4-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-(morpholin-4-yl)-1H-benzimidazol-6-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide, ... (4 entities in total)
• Functional Keywords: kinase, irak4, irak1, irak2, irak3, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 146724.51

Authors

Yu, C.,Drobnick, J.,Bryan, M.C.,Kiefer, J.,Lupardus, P.J. (deposition date: 2019-03-13, 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

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: 31082230
DOI: 10.1021/acs.jmedchem.9b00439

Experimental method

X-RAY DIFFRACTION (1.98 Å)