ART-558

ART-558 is a potent, selective, allosteric small molecule inhibitor of DNA polymerase theta (Polθ, also known as POLQ), developed by Artios Pharma. It targets the DNA repair protein Polθ, which is essential for the Theta-Mediated End Joining (TMEJ) pathway. By inhibiting TMEJ, ART-558 exploits synthetic lethality in tumor cells deficient in homologous recombination (HR), such as those with BRCA1 or BRCA2 mutations. Preclinical studies have demonstrated its efficacy in breast cancer, ovarian cancer, and glioblastoma models, both as a monotherapy and in combination with PARP inhibitors to overcome resistance mechanisms. The compound has an IC50 of 7.9 nM and elicits DNA damage specifically in HR-deficient tumor cells.