ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin.

摘要: The realization, that the androgen receptor (AR) is essential for prostate cancer (PC) even after relapse following deprivation therapy motivated search novel types of AR inhibitors. We proposed targeting expression versus its function would work in cells having either wild type or mutant as well be independent synthesis pathways. Previously, using a phenotypic screen androgen-independent PC we identified small molecule inhibitor AR, ARTIK-52. Treatment with ARTIK-52 caused loss protein and death AR-positive, but not AR-negative, cells. Here present data induces degradation mRNA through mechanism were unable to establish. However, found toxic breast (BC) expressing although they sensitive knockdown, suggesting an AR-independent toxicity. Using different approaches detected replication-dependent double strand DNA breaks exclusively origin, while causing damage, any toxicity, normal cells, non-PC non-BC tumor their proliferation status. This amazing specificity, combined such basic makes potentially useful tool discover attractive targets treatment BC PC. Thus, screening allowed us identify compound, whose properties cannot predicted based on existing knowledge moreover, uncover barely known link between damage response epithelial