Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin‑1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases

Interleukin-1 receptor-associated
kinase 4 (IRAK4) is
a promising
therapeutic target in inflammation-related diseases. However, the
inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory
efficacy owing to the dual role of IRAK4 as an active kinase and a
scaffolding protein. Herein, we report the design, synthesis, and
biological evaluation of an efficient and selective IRAK4 proteolysis-targeting
chimeric molecule that eliminates IRAK4 scaffolding functions. The
most potent compound, LC-MI-3, effectively degraded cellular IRAK4,
with a half-maximal degradation concentration of 47.3 nM. LC-MI-3
effectively inhibited the activation of downstream nuclear factor-κB
signaling and exerted more potent pharmacological effects than traditional
kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic
effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with
kinase inhibitors in vivo. Therefore, LC-MI-3 is
a candidate IRAK4 degrader in alternative targeting strategies and
advanced drug development.