Discovery of an NF-κB1 p105 Degrader for Anti-Inflammatory Therapy via Structural Optimization of the Coumarin Natural Product Minutuminolate

In this study, the coumarin natural product minutuminolate (<b>MNT</b>) was used as a starting point for the development of anti-inflammatory agents. Through structure-activity relationship studies, a lead compound <b>MD-1</b> was designed and synthesized, exhibiting significantly improved anti-inflammatory activities. Mechanistic studies revealed that <b>MD-1</b> is a degrader of the p105 subunit of NF-κB. Gene knockdown experiments further showed that the Cullin-ring ligase (CRL) SCF^βTrCP is involved in <b>MD-1</b>-induced p105 degradation. This leads to suppressed NF-κB transcriptional activity, which is consistent with its potent anti-inflammatory effects. Taken together, our work challenges the longstanding notion that NF-κB is undruggable, as we demonstrate that the p105 subunit of NF-κB is indeed tractable with small molecules. More importantly, our study highlights that natural products are valuable starting points for the discovery and development of anti-inflammatory agents with novel mechanisms of action.