7QG2

IRAK4 in complex with inhibitor

7QG2 の概要

• エントリーDOI: 10.2210/pdb7qg2/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, 6-methyl-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)
• 機能のキーワード: kinase inhibitor interleukin-1 receptor-associated kinase 4 interleukin-1 signaling, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 140174.03

構造登録者

Xue, Y.,Aagaard, A.,Robb, G.R.,Degorce, S.L. (登録日: 2021-12-07, 公開日: 2022-05-04, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.031 Å)