Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death

By integrating growth pathways on which cancer cells rely, steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) represent emerging targets in cancer therapeutics. High-throughput screening for SRC small molecule inhibitors (SMIs) uncovered MCB-613 as a potent SRC small molecule “stimulator” (SMS). We demonstrate that MCB-613 can super-stimulate SRCs’ transcriptional activity. Further investigation revealed that MCB-613 increases SRCs’ interactions with other coactivators and markedly induces ER stress coupled to the generation of reactive oxygen species (ROS). Because cancer cells overexpress SRCs and rely on them for growth, we show that we can exploit MCB-613 to selectively induce excessive stress in cancer cells. This suggests that over-stimulating the SRC oncogenic program can be an effective strategy to kill cancer cells. [Display omitted] •The small molecule compound MCB-613 super-stimulates SRC transcriptional activity•Acute hyper-activation of SRCs by MCB-613 leads to aberrant cellular stress•MCB-613 selectively kills cancer cells and inhibits tumor growth in vivo•Over-activation of SRCs is a potential alternative strategy for cancer therapy Wang et al. identify MCB-613 as a potent steroid receptor coactivator (SRC) small molecule stimulator. They show that, paradoxically, acute super-activation of SRCs specifically and effectively kills cancer cells by inducing aberrant cellular stress, suggesting an alternative strategy against cancer.