6THW

IRAK4 in complex with inhibitor

6THW の概要

• エントリーDOI: 10.2210/pdb6thw/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, 7-fluoranyl-4-(1-methylcyclopropyl)oxy-~{N}-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-6-(2-methylpyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-amine (3 entities in total)
• 機能のキーワード: irak4, kinase, inhibitor, cancer, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69929.20

構造登録者

Xue, Y.,Aagaard, A.,Degorce, S.L. (登録日: 2019-11-21, 公開日: 2020-10-28, 最終更新日: 2024-05-01)

主引用文献

Degorce, S.L.,Aagaard, A.,Anjum, R.,Cumming, I.A.,Diene, C.R.,Fallan, C.,Johnson, T.,Leuchowius, K.J.,Orton, A.L.,Pearson, S.,Robb, G.R.,Rosen, A.,Scarfe, G.B.,Scott, J.S.,Smith, J.M.,Steward, O.R.,Terstiege, I.,Tucker, M.J.,Turner, P.,Wilkinson, S.D.,Wrigley, G.L.,Xue, Y.
Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.
Bioorg.Med.Chem., 28:115815-115815, 2020

PubMed Abstract: In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.

PubMed: 33091850
DOI: 10.1016/j.bmc.2020.115815

実験手法

X-RAY DIFFRACTION (2.44 Å)