This study explores PROTACs for NLRP3, the key player in innate immunity. We utilised a thiophene analogue of the NLRP3 inhibitor MCC950 and employed CuAAC chemistry for the assembly of PROTACs bearing various linkers and recruiting three different E3 ligases. Compounds were evaluated in bidirectional thermal stability studies with NLRP3 and E3 ligases. IL-1β release and protein abundance of NLRP3 were assessed in cellular assays. PROTAC V2 induces a significant VHL-dependent degradation of NLRP3 and constitutes a valuable tool to decipher the intricate details of the NLRP3 inflammasome.
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