In terms of serine/glycine metabolism, breast cancers (BRCA) can largely be divided into serine/glycine uptake or synthesis addicted. Using a yeast model system that upregulates serine/glycine synthesis, we selected repurposed compounds that target serine/glycine synthesis in the breast cancer context. After thorough in vitro validation, the most promising, and clinically used, repurposed compound was selected for the rational design of a novel combination therapy for serine/glycine synthesis addicted breast cancer. Human enzymes involved in serine/glycine synthesis are indicated in blue. PHGDH: phosphoglycerate dehydrogenase; PSAT1: phosphoserine aminotransferase; PSPH: phosphoserine phosphatase; SHMT1/2: cytosolic/mitochondrial serine hydroxymethyltransferase; TCA: tricarboxylic acid.