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

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.

Automated summary

Propafenone, an FDA-approved antiarrhythmic medication, has been found to effectively inhibit the viability and homologous recombination pathway of conjunctival melanoma (CM) cells. The derivative D34, with promising structure-activity relationships, strongly suppressed CM cell proliferation, viability, and migration. Mechanistically, D34 increased gamma-H2AX nuclear foci and DNA damage by inhibiting the homologous recombination pathway, especially the MRE11-RAD50-NBS1 complex. Moreover, D34 dihydrochloride significantly suppressed tumor growth in a CM xenograft model without toxicity. This discovery suggests that propafenone derivatives targeting the MRE11-RAD50-NBS1 complex may provide a potential approach for CM therapy and enhance chemo- and radio-sensitivity.