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 (MNT) was used as a starting point for the development of anti-inflammatory
agents. Through structure–activity relationship studies, a
lead compound MD-1 was designed and synthesized, exhibiting
significantly improved anti-inflammatory activities. Mechanistic studies
revealed that MD-1 is a degrader of the p105 subunit
of NF-κB. Gene knockdown experiments further showed that the
Cullin-ring ligase (CRL) SCFβTrCP is involved in MD-1-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.