NU1774

NU1774 is a potent and selective small molecule inhibitor of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in the non-homologous end joining (NHEJ) pathway of DNA double-strand break repair. Developed by the Newcastle University Drug Discovery Unit, NU1774 is being investigated for its potential to overcome immune evasion in aggressive neuroendocrine malignancies, particularly small cell lung cancer (SCLC). By inhibiting DNA-PKcs, NU1774 restores the expression of major histocompatibility complex class I (MHC-I) and antigen presentation machinery (such as TAP1 and TAP2), which are frequently repressed in SCLC. Furthermore, the compound activates the cGAS-STING pathway, leading to increased CD8+ T-cell infiltration and enhanced anti-tumor immunity. Preclinical studies demonstrate that NU1774 synergizes with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, to promote significant tumor regression in aggressive murine models of SCLC.