Indolequinone-Based Hypoxia-Activated Proteolysis Targeting Chimeras Selectively Degrade BRD4 in Hypoxic Cancer Cells.

ABSTRACT: Proteolysis targeting chimeras (PROTACs) have helped to establish proximity induction as an exciting strategy in drug discovery, and there are multiple clinical trials focused on this modality. However, degradation of a full protein in a physiological setting might lead to dose-limiting toxicities, giving rise to the need for PROTACs that are activated in a context-dependent nature. Here, we report the development of hypoxia-activated PROTACs (HAP-TACs) which are selectively activated in conditions of low oxygen (hypoxia) such as those found in solid tumors. To develop HAP-TACs, we have attached an indolequinone bioreductive group to an essential functional group of either the VHL- or cereblon-recruiting component of the PROTAC, reducing affinity for its cognate E3 ligase and preventing de

SUBMITTER: Serafini M 

PROVIDER: S-EPMC12512183 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature