Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors

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 radio-sensitivity 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Inhibiting SENP1 can enhance the sensitivity of cancer cells to radiation, making it a promising target for radiosensitization. A total of 53 pentacyclic triterpene derivatives were designed and synthesized as SENP1 inhibitors, with ten derivatives showing better inhibitory activities than the original compound. Compound 36 exhibited the best radiosensitizing activity among the derivatives tested in this study.