Discovery of Rigid Linker-Based IRAK4 PROTACs with Improved Metabolic Stability for the Treatment of Inflammatory Diseases

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target for inflammatory diseases. However, solely inhibiting IRAK4 kinase activity fails to fully block inflammatory signaling, resulting in limited efficacy. Herein, we describe the design and synthesis of novel IRAK4 degraders based on a proteolysis-targeting chimera (PROTAC) strategy. The preferred compound, <b>FIP22</b>, effectively degraded cellular IRAK4 with a DC₅₀ of 3.2 nM, 115-fold higher than the lead compound <b>DE5</b>. Mechanistically, <b>FIP22</b> induces the ubiquitin-proteasome system by forming an IRAK4-<b>FIP22</b>-CRBN ternary complex, thereby potently blocking IRAK4-mediated NF-κB and MAPK signaling pathways. Concurrently, <b>FIP22</b> demonstrated favorable safety profiles and excellent metabolic stability (e.g., 180-fold longer half-life than the lead compound <b>DE5</b>). Furthermore, <b>FIP22</b> exhibited significant therapeutic efficacy in a 2,4-dinitrochlorobenzene-induced atopic dermatitis mouse model. In summary, <b>FIP22</b> represents a candidate IRAK4 degrader for alternative targeting strategies and advanced drug development.