2. Academic Validation
  3. Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

  • J Med Chem. 2024 Jan 25;67(2):1225-1242. doi: 10.1021/acs.jmedchem.3c01714.
Ulrich Bothe 1,  Judith Günther 1,  Reinhard Nubbemeyer 1,  Holger Siebeneicher 1,  Sven Ring 1,  Ulf Bömer 1,  Michaele Peters 1,  Alexandra Rausch 1,  Karsten Denner 1,  Herbert Himmel 1,  Andreas Sutter 1,  Ildiko Terebesi 1,  Martin Lange 1,  Antje M Wengner 1,  Nicolas Guimond 1,  Tobias Thaler 1,  Johannes Platzek 1,  Uwe Eberspächer 1,  Martina Schäfer 1,  Holger Steuber 1,  Thomas M Zollner 1,  Andreas Steinmeyer 1,  Nicole Schmidt 1
Affiliations

Affiliation

  • 1 Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.
PMID: 38228402 DOI: 10.1021/acs.jmedchem.3c01714
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.

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