Significance Glioblastoma (GBM) cells develop intrinsic or acquired insensitiveness to BET bromodomain inhibitors (BBIs) yet develop persistent BET protein dependency. Selective degradation of BET proteins by a next-generation chemical compound undermines the BET protein dependency and exerts superior antineoplastic effects over inhibition of BET bromodomain. Given the significant difference between bromodomain dependency and BET protein dependency in GBM cells, chemically induced degradation of BET proteins serves as a promising strategy to overcome anticipated clinical BBIs resistance.