Synthesis and <i>in vitro</i> 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. <i>In silico</i> 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.