8BR5

Discovery of IRAK4 Inhibitor 41

This is a non-PDB format compatible entry.

Summary for 8BR5

• Entry DOI: 10.2210/pdb8br5/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, ~{N}-[2,3-dimethyl-6-(1~{H}-pyrazol-5-yl)benzimidazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: irak4, kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 136681.36

Authors

Schafer, M.,Bothe, U.,Schmidt, N.,Gunther, J.,Nubbemeyer, R.,Siebeneicher, H.,Ring, S.,Boemer, U.,Peters, M.,Denner, K.,Himmel, H.,Sutter, A.,Terebesi, I.,Lange, M.,Wenger, A.M.,Guimond, N.,Thaler, T.,Platzek, J.,Eberspaecher, U.,Steuber, H.,Steinmeyer, A.,Zollner, T.M. (deposition date: 2022-11-22, release date: 2024-01-31, Last modification date: 2024-11-06)

Primary citation

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.
Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839 .
J.Med.Chem., 67:1225-1242, 2024

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, (zabedosertib) and , 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.

PubMed: 38228402
DOI: 10.1021/acs.jmedchem.3c01714

Experimental method

X-RAY DIFFRACTION (2.7 Å)