Background:

SCR7 pyrazine is an inhibitor of DNA ligase IV [1].

DNA Ligase IV is involved in sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). DSBs have been considered as one of the most lethal types of DNA damage within cells. Unrepaired DSBs may lead to chromosomal rearrangements such as translocations and deletions, resulting in oncogenic transformations or cell death. In higher eukaryotes, NHEJ is one of the primary mechanisms of DSB repair and is active throughout the cell cycle. NHEJ plays a major role in providing resistance to cancer cells to these radio- and chemotherapy agents [1].

SCR7 blocked Ligase IV-mediated joining by interfering with its DNA binding in cell-free repair system. SCR7 inhibited NHEJ in a Ligase IV-dependent manner within cells, and activated the intrinsic apoptotic pathway. SCR7 dose-dependent decreased cell proliferation in MCF7, A549, and HeLa cells with an IC50 of 40, 34, and 44 μM, respectively. In T47D, A2780, and HT1080 cells, the IC50 values were 8.5, 120, and 10 μM, respectively [1].

SCR7 treatment (10 mg/kg, six doses) significantly reduced breast adenocarcinoma-induced tumor and impeded tumor progression in mouse models in mouse models. Coadministered of SCR7 with DSB-inducing therapeutic modalities significantly enhanced their sensitivity.

Reference:
[1] Srivastava M, Nambiar M, Sharma S, et al.  An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression[J]. Cell, 2012, 151(7): 1474-1487.