Synthesis and in vitro characterization of novel IRAK-4 inhibitor compounds

IRAK-4 plays a crucial role in autoimmune diseases, cancer and severe infections like sepsis. Inhibition of IRAK-4 may help manage these conditions. This study synthesized and evaluated four novel compounds (IGYZT01046, IGYZT01058, IGYZT01066, and IGYZT01068) for their IRAK-4 inhibitory potential. Molecular docking results showed all compounds had strong binding affinities for IRAK-4, with binding energies below −9.5 kcal/mol, indicating favorable interactions. Enzyme profiling confirmed their potential to target kinase enzymes, including IRAK-4. The compounds were synthesized and their structures were verified by NMR spectroscopy. Among them, IGYZT01058 was the most potent inhibitor, with an IC50 value of 5.32 nM in biochemical assays. All compounds displayed significant inhibitory activity with IC50 values below 100 nM, making them suitable for further development. In silico ADME predictions indicated promising pharmacokinetic properties, including good intestinal absorption and blood-brain barrier penetration. Overall, the study confirms that all four compounds as strong IRAK-4 inhibitors, with IGYZT01058 standing out as the most potent, suggesting its potential as a therapeutic agent for autoimmune diseases and sepsis.