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.

本研究以香豆素类天然产物minutuminolate（MNT）为研发起点，开展抗炎药物开发工作。通过构效关系研究，设计并合成得到先导化合物MD-1，其抗炎活性显著提升。机制研究揭示，MD-1可作为核因子κB（NF-κB）p105亚基的降解剂。后续基因敲低实验进一步证实，Cullin环连接酶（CRL）SCFβTrCP参与了MD-1诱导的p105降解过程。该过程可抑制NF-κB的转录活性，这与其强效抗炎效应一致。综上，本研究挑战了长期以来‘NF-κB不可成药’的固有认知，证实NF-κB的p105亚基确实可通过小分子药物实现靶向调控。更为重要的是，本研究凸显了天然产物作为发现与开发具有全新作用机制抗炎药物的宝贵研发起点。