Angiosarcoma is a rare soft tissue sarcoma originating from endothelial cells. Given that current treatments for advanced disease have shown limited efficacy, alternative therapies need to be identified. In rare diseases, patient-derived cell models are crucial for screening anti-tumour activity. In this study, cell line models were characterised in 2D and 3D cultures. The cell lines’ growth, migration and invasion capabilities were explored, confirming them as useful tools for preclinical angiosarcoma studies. By screening a drug library, we identified potentially effective compounds: 8-amino adenosine impacted cell growth and inhibited migration and invasion at considerably low concentrations as a single agent. No synergistic effect was detected when combining with paclitaxel, gemcitabine or doxorubicin. These results suggest that this compound could be a potentially useful drug in the treatment of AGS. Display omitted •2 and 3D cellular models of AGS constitute a promising in vitro drug screening tool.•Several compounds have been validated as effective in AGS cell lines.•8AA would be the most interesting drug with which to continue development in AGS.•8AA shows promising anti-tumour activity in vitro.•8AA demonstrated in vitro proliferation, migration and invasion inhibition.