8ATB

Discovery of IRAK4 Inhibitor 16

これはPDB形式変換不可エントリーです。

8ATB の概要

• エントリーDOI: 10.2210/pdb8atb/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, ~{N}-[6-ethoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxidanylidene-ethyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: irak4, kinase, transferase
• 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: 67710.21

構造登録者

Schafer, M.,Bothe, U.,Schmidt, N.,Gunther, J.,Nubbemeyer, R.,Siebeneicher, H.,Ring, S.,Boemer, U.,Peters, M.,Denner, K.,Himmel, H.,Sutter, A.,Terebesi, I.,Lange, M.,Wenger, A.M.,Guimond, N.,Thaler, T.,Platzek, J.,Eberspaecher, U.,Steuber, H.,Steinmeyer, A.,Zollner, T.M. (登録日: 2022-08-22, 公開日: 2023-11-29, 最終更新日: 2026-03-04)

主引用文献

Bothe, U.,Gunther, J.,Nubbemeyer, R.,Siebeneicher, H.,Ring, S.,Bomer, U.,Peters, M.,Rausch, A.,Denner, K.,Himmel, H.,Sutter, A.,Terebesi, I.,Lange, M.,Wengner, A.M.,Guimond, N.,Thaler, T.,Platzek, J.,Eberspacher, U.,Schafer, M.,Steuber, H.,Zollner, T.M.,Steinmeyer, A.,Schmidt, N.
Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839 .
J.Med.Chem., 67:1225-1242, 2024

PubMed Abstract: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, (zabedosertib) and , starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

PubMed: 38228402
DOI: 10.1021/acs.jmedchem.3c01714

実験手法

X-RAY DIFFRACTION (2.35 Å)