Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells

Manipulation of protein stability with small molecules has a great potential for both basic research and clinical therapy. Recently, we have developed a series of hybrid small molecules named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser) that induces degradation of target proteins via ubiquitin-proteasome system. Here we report the activities of SNIPER(ER) that targets estrogen receptor alpha (ER) for degradation. SNIPER(ER) induced degradation of ER and inhibited estrogen-dependent expression of pS2 gene in an estrogen-dependent breast cancer cell line MCF-7. A proteasome inhibitor MG132 and siRNA-mediated downregulation of cIAP1 abrogated the SNIPER(ER)-induced ER degradation, suggesting that the ER is degraded by proteasome subsequent to cIAP1-mediated ubiquitylation. Intriguingly, after the ER degradation, the SNIPER(ER)-treated MCF-7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, a marker of necrosis, from the cells. Following the ER degradation, reactive oxygen species (ROS) was produced in the SNIPER(ER)-treated MCF-7 cells, and an anti-oxidant N-acetylcysteine inhibited the necrotic cell death. These results indicate that SNIPER(ER) induces ER degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ER-positive breast cancers.