SAR study of celastrol analogs targeting Nur77-mediated inflammatory pathway

Ziwen Chen; Duo Zhang; Siwei Yan; Chaochao Hu; Zhenfei Huang; Zhuoer Li; Shuangzhou Peng; Xiaotong Li; Yi Zhu; Hongyu Yu; Baohuan Lian; Qi Kang; Mingyu Li; Zhiping Zeng; Xiao-Kun Zhang; Ying Su

doi:10.1016/j.ejmech.2019.05.009

SAR study of celastrol analogs targeting Nur77-mediated inflammatory pathway

Eur J Med Chem. 2019 Sep 1:177:171-187. doi: 10.1016/j.ejmech.2019.05.009. Epub 2019 May 12.

Authors

Ziwen Chen¹, Duo Zhang¹, Siwei Yan¹, Chaochao Hu¹, Zhenfei Huang¹, Zhuoer Li¹, Shuangzhou Peng¹, Xiaotong Li¹, Yi Zhu¹, Hongyu Yu¹, Baohuan Lian¹, Qi Kang¹, Mingyu Li¹, Zhiping Zeng¹, Xiao-Kun Zhang², Ying Su³

Affiliations

¹ School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, 361002, China.
² School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, 361002, China. Electronic address: xkzhang@xmu.edu.cn.
³ School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, 361002, China; Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA, 92037, USA. Electronic address: ysu@sbpdiscovery.org.

PMID: 31132532
DOI: 10.1016/j.ejmech.2019.05.009

Abstract

Nur77, an orphan member of the nuclear receptor superfamily, plays an important role in the regulation of inflammatory processes. Our previous work found that celastrol, a pentacyclic triterpene, bound to Nur77 to inhibit inflammation in a Nur77-dependent manner. Celastrol binding to Nur77 promotes Nur77 translocation from nucleus to cytoplasm, resulting in clearance of inflamed mitochondria and then alleviation of inflammation. Here, we report the design, synthesis, SAR study and biological evaluation of a series of celastrol analogs. A total of 24 celastrol derivatives were made. Compound 3a with a K_d of 0.87 μM was found to be less toxic than celastrol and could be a hit molecule for further optimization.

Keywords: Anti-inflammatory; Celastrol; Celastrol derivatives; Nur77; SAR.

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / pharmacology*
Anti-Inflammatory Agents / toxicity
Binding Sites
Drug Design
Hep G2 Cells
Humans
Molecular Docking Simulation
Molecular Structure
Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors*
Nuclear Receptor Subfamily 4, Group A, Member 1 / chemistry
Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
Pentacyclic Triterpenes
Protein Binding / drug effects
Sequestosome-1 Protein / metabolism
Structure-Activity Relationship
TNF Receptor-Associated Factor 2 / metabolism
Triterpenes / chemical synthesis
Triterpenes / metabolism
Triterpenes / pharmacology*
Triterpenes / toxicity
Zebrafish

Substances

Anti-Inflammatory Agents
NR4A1 protein, human
Nuclear Receptor Subfamily 4, Group A, Member 1
PSMD2 protein, human
Pentacyclic Triterpenes
SQSTM1 protein, human
Sequestosome-1 Protein
TNF Receptor-Associated Factor 2
Triterpenes
celastrol