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

  • J Med Chem. 2025 Jun 12;68(11):11081-11099. doi: 10.1021/acs.jmedchem.5c00055.
Malcolm Z Y Choo  1 ,  En Tong Lim  1 ,  W S Fred Wong  2  3 ,  Christina L L Chai  1
Affiliations
  • 1. Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543 Singapore.
  • 2. Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600 Singapore.
  • 3. Drug Discovery and Optimization Platform, Yong Loo Lin School of Medicine, National University Health System, 117600 Singapore.
PMID: 40378174 DOI: 10.1021/acs.jmedchem.5c00055
Abstract

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.

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