7QG3

IRAK4 in complex with inhibitor

Summary for 7QG3

• Entry DOI: 10.2210/pdb7qg3/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, 6-[(2~{S})-2-fluoranylpropyl]-4-[(1-methylcyclopropyl)amino]-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one (3 entities in total)
• Functional Keywords: kinase inhibitor interleukin-1 receptor-associated kinase 4 interleukin-1 signaling, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70339.06

Authors

Xue, Y.,Aagaard, A.,Robb, G.R.,Degorce, S.L. (deposition date: 2021-12-07, release date: 2022-05-04, Last modification date: 2024-01-31)

Primary citation

Cumming, I.A.,Degorce, S.L.,Aagaard, A.,Braybrooke, E.L.,Davies, N.L.,Diene, C.R.,Eatherton, A.J.,Felstead, H.R.,Groombridge, S.D.,Lenz, E.M.,Li, Y.,Nai, Y.,Pearson, S.,Robb, G.R.,Scott, J.S.,Steward, O.R.,Wu, C.,Xue, Y.,Zhang, L.,Zhang, Y.
Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors.
Bioorg.Med.Chem., 63:116729-116729, 2022

PubMed Abstract: In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.

PubMed: 35439688
DOI: 10.1016/j.bmc.2022.116729

Experimental method

X-RAY DIFFRACTION (2.11 Å)