Ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases mediate the DNA damage response pathway in cells upon encounter with genotoxic agents. Their signaling can activate cell cycle arrest, DNA repair, induction of premature senescence, and cell death. Inhibiting this pathway is one strategy implemented to increase the therapeutic capacity of certain genotoxic anti-cancer regimens by sensitizing cancer cells to these agents. CGK733, a thiourea-containing compound, was originally identified as a specific inhibitor of ATR and ATM kinases (IC50 = ~ 200 nM). In prematurely senescent breast, lung, and colon cancer cells CGK733 reportedly suppresses ATM-mediated p21 expression required for survival, resulting in cell death. Human cancer cell lines exposed to both caffeine and CGK733 demonstrate a rapid decline in cyclin D1 protein levels and a reduction in retinoblastoma protein levels, which leads to the inhibition of their proliferation.
