Development of the First-in-Class Degrader of NLRP3

Targeted protein degradation, spearheaded by proteolysis targeting chimeras (PROTACs), has emerged as an auspicious avenue for drug discovery. NLRP3, a key player in innate immunity associated with several inflammatory diseases, has not yet been targeted by PROTACs. This study explores NLRP3 PROTACs as potential therapeutic candidates. We exploited the diaryl sulfonylurea pharmacophore and utilized a thiophene analog of the NLRP3 inhibitor MCC950 for PROTAC assembly. Using CuAAC chemistry, heterobifunctional degraders bearing various linkers and recruiting three different E3 ligases were synthesized. The compounds were evaluated in bidirectional thermal stability assays with NLRP3 and E3 ligases and their cellular activity was determined by assessing IL-1β release and protein abundance of NLRP3, respectively. PROTAC V2 induces a significant VHL-dependent degradation of NLRP3 and constitutes a valuable tool compound for future biomedical research to decipher the intricate details of the NLRP3 inflammasome.