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.
School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Eur J Med Chem. 2022 Jan 5;227:113918. doi: 10.1016/j.ejmech.2021.113918. Epub 2021 Oct 14.
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.
SUMOylation 和 deSUMOylation 在 DNA 损伤反应和放射治疗抵抗的形成中起着重要作用。SENP1 是主要的特异性异肽酶，可催化 deSUMOylation 修饰。抑制 SENP1 可上调癌细胞的放射敏感性，使其成为放射增敏的有前途的靶点。在此，基于熊果酸（UA）的结构，共设计和合成了 53 种五环三萜衍生物作为 SENP1 抑制剂。其中 10 种衍生物对 SENP1 的抑制活性优于 UA，并对初步的构效关系进行了探讨。大多数 UA 衍生物的细胞毒性较低，其中化合物 36 表现出最好的放射增敏活性，SER 值为 1.45。这是首次开发小分子 SENP1 抑制剂作为放射增敏剂的研究。
