2. Academic Validation
  3. Drug repurposing of propafenone to discover novel anti-tumor agents by impairing homologous recombination to delay DNA damage recovery of rare disease conjunctival melanoma

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

  • Eur J Med Chem. 2023 Mar 15;250:115238. doi: 10.1016/j.ejmech.2023.115238.
Jinlian Wei 1,  Yongyun Li 2,  Ruoxi Li 1,  Xin Chen 1,  Tiannuo Yang 1,  Liang Liao 1,  Yuqing Xie 1,  Jin Zhu 1,  Fei Mao 1,  Renbing Jia 3,  Xiaofang Xu 4,  Jian Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • 2 Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 3 Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 4 Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, Dali, 671000, China; Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China; Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou, 570228, Hainan, China. Electronic address: [email protected].
PMID: 36868105 DOI: 10.1016/j.ejmech.2023.115238
Abstract

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 suppressed the proliferation, viability, and migration of CM cells at submicromolar concentrations. Mechanically, D34 had the potential to increase γ-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 significantly 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.

Keywords

Conjunctival melanoma; DNA damage; Homologous recombination; MRE11-RAD50-NBS1 complex; Propafenone.

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