2. Academic Validation
  3. SAR study of celastrol analogs targeting Nur77-mediated inflammatory pathway

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.
Ziwen Chen 1,  Duo Zhang 1,  Siwei Yan 1,  Chaochao Hu 1,  Zhenfei Huang 1,  Zhuoer Li 1,  Shuangzhou Peng 1,  Xiaotong Li 1,  Yi Zhu 1,  Hongyu Yu 1,  Baohuan Lian 1,  Qi Kang 1,  Mingyu Li 1,  Zhiping Zeng 1,  Xiao-Kun Zhang 2,  Ying Su 3
Affiliations

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 Kd 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.

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