Discovery of estrogen receptor α targeting caged hypoxia-responsive PROTACs with an inherent bicyclic skeleton for breast cancer treatment

•The first ERα-targeted hypoxia-responsive PROTACs were developed.•These PROTACs showed excellent hypoxic response and low toxicity in normal cells.•PROTAC 8a showed potent antiproliferative activities under hypoxic conditions in tamoxifen-sensitive and -resistant breast cancer cells.•The ERα degradation activity of these PROTACs was achieved through the ubiquitin–proteasome pathway.