Discovery of
IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

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

doi:10.1021/acs.jmedchem.3c01714.s002

jm3c01714_si_002.pdf (2.27 MB)

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

journal contribution

posted on 2024-01-17, 01:14 authored by Ulrich Bothe, Judith Günther, Reinhard Nubbemeyer, Holger Siebeneicher, Sven Ring, Ulf Bömer, Michaele Peters, Alexandra Rausch, Karsten Denner, Herbert Himmel, Andreas Sutter, Ildiko Terebesi, Martin Lange, Antje M. Wengner, Nicolas Guimond, Tobias Thaler, Johannes Platzek, Uwe Eberspächer, Martina Schäfer, Holger Steuber, Thomas M. Zollner, Andreas Steinmeyer, Nicole Schmidt

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.