文献类型：期刊文献

英文题名：Drug repurposing of propafenone to discover novel anti-tumor agents by impairing homologous recombination to delay DNA damage recovery of rare disease conjunctival melanoma

作者：Wei, Jinlian[1];Li, Yongyun[2];Li, Ruoxi[1];Chen, Xin[1];Yang, Tiannuo[1];Liao, Liang[1];Xie, Yuqing[1];Zhu, Jin[1];Mao, Fei[1];Jia, Renbing[2];Xu, Xiaofang[2];Li, Jian[1,3,4,5]

机构：[1]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Pharm,State Key Lab Bioreactor Engn,Shanghai F, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, Peoples Hosp 9, Sch Med, Dept Ophthalmol, Shanghai 200025, Peoples R China;[3]Dali Univ, Coll Pharm, Yunnan Key Lab Screening & Res Antipathogen Plant, Dali 671000, Peoples R China;[4]Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Clin Med Sci & Tech Innovat Ctr, Shanghai 200092, Peoples R China;[5]Hainan Univ, Coll Pharm, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Hainan, Peoples R China

年份：2023

卷号：250

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000954392300001)】；

基金：This work was supported by the National Natural Science Foundation of China (82003603, 81872747) , the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212702) , the National Special Fund for State Key Laboratory of Bioreactor Engineering (2060204) , Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28) .

语种：英文

外文关键词：Conjunctival melanoma; Propafenone; Homologous recombination; DNA damage; MRE11-RAD50-NBS1 complex

摘要：Conjunctival melanoma (CM), a rare and fatal malignant ocular tumor, lacks proper diagnostic biomarkers and therapy. Herein, we revealed the novel application of propafenone, an FDA-approved antiarrhythmic medication, which was identified effective in inhibiting CM cells viability and homologous recombination pathway. Detailed structure-activity relationships generated D34 as one of the most promising derivatives, which strongly sup -pressed the proliferation, viability, and migration of CM cells at submicromolar concentrations. Mechanically, D34 had the potential to increase gamma-H2AX nuclear foci and aggravated DNA damage by suppressing homologous recombination pathway and its factors, particularly the complex of MRE11-RAD50-NBS1. D34 bound to human recombinant MRE11 protein and inhibited its endonuclease activity. Moreover, D34 dihydrochloride signifi-cantly suppressed tumor growth in the CRMM1 NCG xenograft model without obvious toxicity. Our finding shows that propafenone derivatives modulating the MRE11-RAD50-NBS1 complex will most likely provide an approach for CM targeted therapy, especially for improving chemo-and radio-sensitivity for CM patients.