2. Academic Validation
  3. New Highly Potent NLRP3 Inhibitors: Furanochalcone Velutone F Analogues

New Highly Potent NLRP3 Inhibitors: Furanochalcone Velutone F Analogues

  • ACS Med Chem Lett. 2022 Mar 7;13(4):560-569. doi: 10.1021/acsmedchemlett.1c00597.
Ruijia Zhang 1,  Feng Hong 1,  Min Zhao 2,  Xiaoying Cai 1,  Xueqin Jiang 1,  Neng Ye 1,  Kaiyue Su 1,  Na Li 1,  Minghai Tang 1,  Xu Ma 1,  Hengfan Ni 3,  Lun Wang 1,  Li Wan 3,  Lijuan Chen 1,  Wenshuang Wu 4 5,  Haoyu Ye 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 2 Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of TCM, Chengdu 610041, China.
  • 4 Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
  • 5 Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 35450356 DOI: 10.1021/acsmedchemlett.1c00597
Abstract

The NLRP3 inflammasome has now emerged as one of the most appealing drug targets for many inflammation-related diseases. Velutone F, a natural NLPR3 inhibitor, identified in our previous study has been limited in application by its low in planta abundance, weak activity, and complicated synthetic routes. To address these needs, structural optimization of velutone F led to a series of novel NLRP3 inhibitors. Among them, compound 14c exerted remarkable inhibitory activity with an IC50 value in the nanomolar range (251.1 nM) and was approximately 5-fold more potent than velutone F. Moreover, the synthesis method of 14c was simple, easy to handle, and scalable. Compound 14c could suppress NLRP3 inflammasome activation by attenuating ASC speck formation. Most importantly, compound 14c reduced peritoneal neutrophil influx in mice and IL-1β in the spleen in the MSU-induced peritonitis in LPS-primed mouse model. Taken together, compound 14c is a prospective lead compound in the discovery of NLRP3 inflammasome inhibitors.

Figures
Products