NHEJ-P

NHEJ-P is a first-in-class, double-stranded DNA-based proteolysis-targeting chimera (PROTAC) designed for precision radiosensitization. Developed by researchers at Memorial Sloan Kettering Cancer Center, it consists of a 32-bp duplex "DNA bait" coupled to a cereblon-binding E3 ligase ligand. This bifunctional molecule enables the selective proteasomal degradation of DNA ligase IV (LIG4), the terminal ligase of the non-homologous end-joining (NHEJ) pathway. By depleting LIG4, NHEJ-P disrupts DNA double-strand break repair kinetics and enhances radiation-induced cytotoxicity in cancer cells while sparing non-transformed cells. A derivative, t-NHEJ-P, is being developed as a HER2-directed antibody-oligonucleotide conjugate (AOC) for tumor-restricted delivery.