NAR Cancer · 10 authors, 13 centres
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Researchers used computational methods to identify drug-like small molecule inhibitors of the RAD52 protein, which is a target for cancers with BRCA mutations. They found two lead compounds that selectively killed BRCA-mutant cancer cells and optimized one into a more potent and selective set of inhibitors.
This study aimed to develop drug-like inhibitors of the human RAD52 protein, a target for cancers with BRCA1/2 mutations. Using pharmacophore-based informatics and an in silico database, researchers identified six chemical scaffolds. Two initial compounds, Z56 and Z99, were tested. Z56 selectively inhibited RAD52 over RPA and was toxic only to BRCA-mutant cells. Z99 inhibited both RAD52 and RPA, showing toxicity in BRCA-complemented cells. Optimization of the Z99 scaffold yielded six derivatives with improved RAD52 inhibition (IC50 ∼1.3–8 μM) and no increased RPA affinity, which were selectively toxic to BRCA-mutant cells. The study demonstrates a roadmap for developing next-generation cancer therapeutics based on RAD52 inhibition, though it is limited to preclinical laboratory evidence and in vitro/cellular models.
