Beyond Inhibition: Targeted Degradation of NLRP3 by Autophagy-Tethering Bifunctional Compounds as a Therapy for Inflammatory Bowel Disease

Abstract Based on our previous finding that the NLRP3 inhibitor LD5 dually binds LC3 and NLRP3, we elucidated the key functional groups responsible for its engagement with NLRP3. Leveraging this insight, we designed and synthesized a library of bivalent LD5-based autophagy-targeting chimeras (ATTECs), from which M3 emerged as the most potent NLRP3 degrader. We further sought to rationalize this approach by investigating the fundamental pharmacological questions: why develop a degrader from an existing inhibitor and what advantages would such a degrader offer over the inhibitor? Comparative studies in a colitis model clearly established that the degrader M3 achieves sustained anti-inflammatory efficacy, both in vitro and in vivo, outperforming its inhibitor precursor LD5. Our study extends beyond the discovery of a potential degrader for inflammatory bowel disease to demonstrate the crucial long-lasting therapeutic advantage of degraders over inhibitors in treating this condition.