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7QG2

IRAK4 in complex with inhibitor

7QG2 の概要
エントリーDOI10.2210/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
Cited by
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
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (3.031 Å)
構造検証レポート
Validation report summary of 7qg2
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-03-12に公開中

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