6UYA

Crystal structure of Compound 19 bound to IRAK4

Summary for 6UYA

• Entry DOI: 10.2210/pdb6uya/pdb
• Related: 6O8U
• Descriptor: Interleukin-1 receptor-associated kinase 4, N-{2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-6-(morpholin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inflammation, lupus, immunology, inhibitor, cancer, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 146708.21

Authors

Kiefer, J.R.,Bryan, M.C.,Lupardus, P.J.,Zarrin, A.A.,Rajapaksa, N.S.,Gobbi, A.,Drobnick, J.,Kolesnikov, A.,Liang, J.,Do, S. (deposition date: 2019-11-12, release date: 2019-11-20, Last modification date: 2024-11-06)

Primary citation

Rajapaksa, N.S.,Gobbi, A.,Drobnick, J.,Do, S.,Kolesnikov, A.,Liang, J.,Chen, Y.,Sujatha-Bhaskar, S.,Huang, Z.,Brightbill, H.,Francis, R.,Yu, C.,Choo, E.F.,DeMent, K.,Ran, Y.,An, L.,Emson, C.,Maher, J.,Wai, J.,McKenzie, B.S.,Lupardus, P.J.,Zarrin, A.A.,Kiefer, J.R.,Bryan, M.C.
Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity.
Acs Med.Chem.Lett., 11:327-333, 2020

PubMed Abstract: IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule that achieves robust in vivo inhibition of cytokines relevant to human disease.

PubMed: 32184965
DOI: 10.1021/acsmedchemlett.9b00380

Experimental method

X-RAY DIFFRACTION (1.74 Å)