학술논문
Discovery of IRAK4 Inhibitors BAY1834845(Zabedosertib) and BAY1830839
Document Type
Article
Author
Bothe, Ulrich; Günther, Judith; Nubbemeyer, Reinhard; Siebeneicher, Holger; Ring, Sven; Bömer, Ulf; Peters, Michaele; Rausch, Alexandra; Denner, Karsten; Himmel, Herbert; Sutter, Andreas; Terebesi, Ildiko; Lange, Martin; Wengner, Antje M.; Guimond, Nicolas; Thaler, Tobias; Platzek, Johannes; Eberspächer, Uwe; Schäfer, Martina; Steuber, Holger; Zollner, Thomas M.; Steinmeyer, Andreas; Schmidt, Nicole
Source
Journal of Medicinal Chemistry; January 2024, Vol. 67 Issue: 2 p1225-1242, 18p
Subject
Language
ISSN
00222623; 15204804
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, BAY1834845(zabedosertib) and BAY1830839, 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.