2. Academic Validation
  3. Discovery of potential novel CRBN modulators by virtual screening and bioassay

Discovery of potential novel CRBN modulators by virtual screening and bioassay

  • Eur J Med Chem. 2022 Jun 5;236:114355. doi: 10.1016/j.ejmech.2022.114355.
Feng Xiong 1,  Lingmei Kong 2,  Liang Chen 2,  Minggao Xue 3,  Feng Cao 2,  Shuqun Zhang 2,  Hongmei Li 2,  Hui Yan 2,  Yan Li 4,  Zhili Zuo 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
  • 3 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming, 650091, China.
  • 4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming, 650091, China. Electronic address: yan.li@ynu.edu.cn.
  • 5 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zuozhili@mail.kib.ac.cn.
PMID: 35413617 DOI: 10.1016/j.ejmech.2022.114355
Abstract

The incidence of malignant tumor with high mortality is increasing yearly. CRBN E3 ubiquitin Ligase was proved to be an antitumor target. It was found that thalidomide and its analogs could bind to CRBN E3 ubiquitin Ligase and modulate CRBN. CRBN modulators could promote the binding of CRBN to specific target proteins or block the binding of CRBN to some endogenous proteins. In this way, CRBN modulators suppress various tumor cells by modulating the interactions between CRBN and various antitumor target proteins. However, almost all CRBN modulators reported include glutarimide scaffold. Therefore, the aim of this study is to developed novel CRBN modulators. Virtual screening methods and bioassay methods, including structural similarity search, molecular docking, substructure search, antitumor evaluation and Apoptosis assay were used to search novel potential CRBN modulators in Specs database. Finally, 15 compounds exhibited strong inhibition activity against A549 cells. Among these active compounds, The IC50 value against A549 of AG6033 was 0.853 ± 0.030 μM. Apoptosis assay demonstrated that AG6033 could promote Apoptosis of A549 cells. Further mechanism studies suggested that AG6033 caused remarkable decrease of GSPT1 and IKZF1, the substrates of CRBN, and AG6033 induced cytotoxic effects was CRBN-dependent.

Keywords

Antitumor evaluation; Apoptosis assay; CRBN modulators; Virtual screening; Western blot.

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