| Structural highlights
Publication Abstract from PubMed
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.
Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839.,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 AM, Guimond N, Thaler T, Platzek J, Eberspacher U, Schafer M, Steuber H, Zollner TM, Steinmeyer A, Schmidt N J Med Chem. 2024 Jan 25;67(2):1225-1242. doi: 10.1021/acs.jmedchem.3c01714. Epub , 2024 Jan 16. PMID:38228402[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bothe U, Günther J, Nubbemeyer R, Siebeneicher H, Ring S, Bömer U, Peters M, Rausch A, Denner K, Himmel H, Sutter A, Terebesi I, Lange M, Wengner AM, Guimond N, Thaler T, Platzek J, Eberspächer U, Schäfer M, Steuber H, Zollner TM, Steinmeyer A, Schmidt N. Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839. J Med Chem. 2024 Jan 25;67(2):1225-1242. PMID:38228402 doi:10.1021/acs.jmedchem.3c01714
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