• ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2- deficient cancer cells, xenograft model and enhances the effects of a PARPi in BRCA deficient cancer cells.• Induces synthetic lethality in PARPi resistance cells with defects in the Shieldin complex.IC50 = 0.5-1.5 μM. This evidence concerns the gene BRCA2 and cancer.