MSC778

MSC778 is a potent, selective, and orally bioavailable small molecule inhibitor of Flap endonuclease 1 (FEN1), a key enzyme in the DNA damage response (DDR) pathway. Developed through a collaboration between Merck KGaA and Artios Pharma, MSC778 leverages synthetic lethal interactions to target homologous recombination-deficient (HRD) cancers, such as those with BRCA mutations, and Ewing sarcoma (EWS) cells, particularly those expressing SLFN11. Mechanistically, the compound enhances FEN1 retention on chromatin and disrupts active DNA replication, resulting in S-phase accumulation and subsequent DNA damage. Preclinical studies have demonstrated that MSC778 can induce tumor stasis in BRCA2-deficient models and potentiate the activity of PARP inhibitors like niraparib.