Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors
Huiqiang Wei1, Jianghong Guo1, Xiao Sun2
1Tianjin 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.
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.
Insights
Scientists developed novel ursolic acid derivatives as SENP1 inhibitors to enhance cancer radiotherapy. Compound 36 showed significant radiosensitizing effects, offering a new strategy for cancer treatment.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- SUMOylation and deSUMOylation are crucial in DNA damage response and radiotherapy resistance.
- SENP1, a key isopeptidase, regulates deSUMOylation and is a potential target for radiosensitization.
Purpose of the Study:
- To design and synthesize novel pentacyclic triterpene derivatives as SENP1 inhibitors.
- To evaluate their potential as radiosensitizers in cancer therapy.
Main Methods:
- Design and synthesis of 53 ursolic acid derivatives.
- In vitro assessment of SENP1 inhibitory activity.
- Evaluation of radiosensitizing effect (SER) and cytotoxicity.
Main Results:
- Ten derivatives demonstrated superior SENP1 inhibitory activity compared to ursolic acid.
- Compound 36 exhibited the most potent radiosensitizing activity (SER=1.45) with low cytotoxicity.
- Preliminary structure-activity relationships were established.
Conclusions:
- Small molecular SENP1 inhibitors based on ursolic acid represent a promising approach for cancer radiosensitization.
- This study is the first to report small molecule SENP1 inhibitors as radiosensitizers.
