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
  • 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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