Download MendeleyDiscovery 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, A.M., Guimond, N., Thaler, T., Platzek, J., Eberspacher, U., Schafer, M., Steuber, H., Zollner, T.M., Steinmeyer, A., Schmidt, N.(2024) J Med Chem 67: 1225-1242
- PubMed: 38228402
- DOI: https://doi.org/10.1021/acs.jmedchem.3c01714
- Primary Citation of Related Structures:
8ATB, 8ATL, 8ATN, 8BR5, 8BR6, 8BR7 - PubMed 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.
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.
Organizational Affiliation:
