Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities

Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy tolerability it is highly desirable improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis optimization. Here, using bromodomain extra-terminal (BET) protein inhibitors (BETi)–a class epigenetic regulators with proven anticancer but clinical development hindered large part by narrow TIs–we introduce a macromolecular prodrug platform overcomes these challenges. Through tuning traceless linkers appended “bottlebrush prodrug” scaffold, we demonstrate correlation vitro kinetics vivo tumor pharmacokinetics, enabling design novel BETi prodrugs enhanced antitumor efficacies devoid dose-limiting toxicities syngeneic triple-negative breast cancer murine model. This work may have immediate implications, introducing potentially overcoming hurdles drug development.