Compound L

Compound L is a novel small molecule inhibitor of the Ku70/80 heterodimer, which serves as the central scaffolding protein for the Non-Homologous End-Joining (NHEJ) DNA double-strand break repair pathway. Discovered through virtual screening of the Ku70/80 crystal structure, Compound L disrupts the protein's binding to DNA substrates with an IC50 of 3.5 μM and inhibits DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity with an IC50 of 2.5 μM. In preclinical models, the compound has demonstrated the ability to synergistically sensitize glioblastoma cells to ionizing radiation. Developed by researchers at the University of Arizona and the University of Tennessee, Compound L is intended for use as a sensitizing agent in combination with radiation or chemotherapy, or as a monotherapy utilizing synthetic lethality in NHEJ-upregulated solid malignancies.