2. Academic Validation
  3. Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors

Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors

  • Eur J Med Chem. 2022 Jan 5:227:113918. doi: 10.1016/j.ejmech.2021.113918.
Huiqiang Wei 1,  Jianghong Guo 1,  Xiao Sun 2,  Wenfeng Gou 1,  Hongxin Ning 1,  Zhennan Fang 1,  Qiang Liu 3,  Wenbin Hou 4,  Yiliang Li 5
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
  • 2 School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
  • 3 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China. Electronic address: liuqiang@irm-cams.ac.cn.
  • 4 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China. Electronic address: houwenbin@irm-cams.ac.cn.
  • 5 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China. Electronic address: liyiliang@irm-cams.ac.cn.
PMID: 34688014 DOI: 10.1016/j.ejmech.2021.113918
Abstract

SUMOylation and deSUMOylation plays an important role in DNA damage response and the formation of radiotherapy resistance. SENP1 is the main specific isopeptidase to catalyze deSUMOylation modification. Inhibiting SENP1 upregulates Cancer cell radiosensitivity and it becomes a promising target for radiosensitization. Herein, based on the structure of ursolic acid (UA), a total of 53 pentacyclic triterpene derivatives were designed and synthesized as SENP1 inhibitors. Ten derivatives exhibited better SENP1 inhibitory activities than UA and the preliminary structure-activity relationship was discussed. Most of the UA derivatives were low-cytotoxic, among which compound 36 showed the best radiosensitizing activity with the SER value of 1.45. It was the first study to develop small molecular SENP1 inhibitors as radiosensitizers.

Keywords

Radiosensitization; SENP1; Semi-synthesis; Structure modification; Structure-activity relationship; Ursolic acid.

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