8DKS

IRAK4 IN COMPLEX WITH COMPOUND #3

8DKS の概要

• エントリーDOI: 10.2210/pdb8dks/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, (1S,2S,3R,4R)-3-({2-[3-(pyrrolidine-1-carbonyl)anilino]thieno[3,2-d]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide, BETA-MERCAPTOETHANOL, ... (4 entities in total)
• 機能のキーワード: kinase inhibitor, irak4, pyrimidine, atp binding, protein binding, 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: 104444.48

構造登録者

Chen, Y.,Lin, N. (登録日: 2022-07-06, 公開日: 2022-08-03, 最終更新日: 2022-08-17)

主引用文献

Chen, Y.,Tso, K.,Heckrodt, T.J.,Li, H.,Yen, R.,Lin, N.,Singh, R.,Taylor, V.,Masuda, E.S.,Park, G.,Payan, D.G.
Bicyclic pyrimidine compounds as potent IRAK4 inhibitors.
Bioorg.Med.Chem.Lett., 73:128900-128900, 2022

PubMed Abstract: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in transduction of IL-1R/TLR signaling which is responsible for innate immune response. From HTS campaign, bicyclic-pyrimidine compounds have been identified as potent IRAK4 inhibitors, exhibiting good potency in both IRAK4 biochemical and LPS induced IL-23 inhibition cell-based assays. The SAR efforts were focused on further improving on-target potency, reducing PAD activities of HTS hit molecule and improving in vivo PK profiles of early lead compounds. When different aromatic rings were fused to the pyrimidine core, and with various substituents at 2- or 4-position of the pyrimidine, the impact on potency and PK properties were observed and are discussed. Selected compounds were further evaluated in IL-1β induced IL-6 inhibition acute animal model and rodent arthritis disease model, of which compounds 33 and 39 showed good efficacy in both studies.

PubMed: 35863718
DOI: 10.1016/j.bmcl.2022.128900

実験手法

X-RAY DIFFRACTION (2.45 Å)