Development of Prostate Cancer-Targeting BRD4 Intramolecular Bivalent Molecular Glue Degraders
Year: 2024
Type: preprint
Abstract: Molecular glue degraders and PROTACs (proteolysis targeting chimeras) are promising therapeutic modalities by hijacking ubiquitin-proteasome pathway to degrade cellular proteins of interests (POIs). However, their clinical applications are often constrained by on-target, off-tissue toxicity. In this study, we present a prostate cancer-targeting delivery strategy for the development of highly potent and selective BRD4 degraders. The tissue-selective degraders are composed of recently reported highly potent BRD4 intramolecular bivalent molecular glue degraders and ligands of prostate-specific membrane antigen (PSMA). The selective degradation of BRD4 was validated both in vitro and in vivo. The mechanism of action was further confirmed through PSMA inhibitor competition. In vivo, selective degradation was observed starting at a dose as low as 1x10-4 mg/kg. This work established a strategy for PSMA targeted delivery of degraders, expanding their potential for clinical applications.
Source: ChemRxiv
Authors: Deqin Cai, Chunrong Li, Malick Bio Idrissou, Nina Hawkins, Ramesh Mudududdla, Xuankun Chen, Thao-Vy Nguyen, Xiaolei Li, Reinier Hernandez, Weiping Tang
Institution: University of Wisconsin–Madison
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: NIH Office of the Director
Award: G2971323730
OpenAlex ID: W4405792482