2. Academic Validation
  3. Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of RORγ antagonists

Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of RORγ antagonists

  • Eur J Med Chem. 2023 Sep 5;257:115472. doi: 10.1016/j.ejmech.2023.115472.
Lianghe Mei 1,  Lansong Xu 2,  Sanan Wu 3,  Yafang Wang 4,  Chao Xu 3,  Lin Wang 3,  Xingyu Zhang 5,  Chengcheng Yu 6,  Hualiang Jiang 7,  Xianglei Zhang 8,  Fang Bai 9,  Chengying Xie 10
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 2 Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
  • 5 China Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, Jiangsu, 215123, China.
  • 6 Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 7 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 8 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China. Electronic address: zhangxl6@shanghaitech.edu.cn.
  • 9 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China. Electronic address: baifang@shanghaitech.edu.cn.
  • 10 Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China. Electronic address: xiecy@lglab.ac.cn.
PMID: 37236000 DOI: 10.1016/j.ejmech.2023.115472
Abstract

Betulinic acid (BA) is a natural pentacyclic triterpenoid that has a wide range of biological and pharmacological effects. Here, computational methods such as pharmacophore screening and reverse docking were used to predict the potential target for BA. Retinoic acid receptor-related orphan receptor gamma (RORγ) was confirmed as its target by several molecular assays as well as crystal complex structure determination. RORγ has been the focus of metabolic regulation, but its potential role in Cancer treatment has only recently come to the fore. In this study, rationale optimization of BA was performed and several new derivatives were generated. Among them, the compound 22 showed stronger binding affinity with RORγ (KD = 180 nM), good anti-proliferative activity against Cancer cell lines, and potent anti-tumor efficacy with a TGI value of 71.6% (at a dose of 15 mg/kg) in the HPAF-II pancreatic Cancer xenograft model. Further RNA-seq analysis and cellular validation experiments supported that RORγ antagonism was closely related to the antitumor activity of BA and 22, resulting in suppression of the Ras/MAPK and Akt/mTORC1 pathway and inducing caspase-dependent Apoptosis in pancreatic Cancer cells. RORγ was highly expressed in Cancer cells and tissues and positively correlated with the poor prognosis of Cancer patients. These results suggest that BA derivatives are potential RORγ antagonists worthy of further exploration.

Keywords

Anti-tumor effects; Betulinic acid; RORγ antagonists; Rationale structure optimization; Target identification.

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