Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

Abstract

Targeted protein degradation is a powerful induced-proximity tool to control cellular concentrations of native proteins using small molecules. However, the design of selectivity in protein degradation remains challenging. In the case of Bromodomain and Extra-Terminal (BET) family proteins, BRD4 has emerged as the primary therapeutic target over other family members BRD2, 3 and T, but strategies to selectively degrade BRD4 rely on the use of pan-BET inhibitors optimized for BRD4:E3 protein-ubiquitin ligase (E3) ternary complex formation. Here, we report a potent and selective inhibitor for the first bromodomain of BRD4, iBRD4-BD1 (IC50 = 12 nM, 23-6200-fold intra-BET selectivity). We further use this novel inhibitor to develop dBRD4-BD1 that induces selective degradation of BRD4 at a DC50 of 280 nM. The design of BRD4 selectivity up-front enables the study of BRD4 biology in the absence of wider BET-inhibition, simplifies design of future BRD4-selective degraders as new E3 recruiting ligands are discovered, and provides a tool to design additional heterobifunctional BRD4-selective probes.

Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

“…Gadd et al showed that the BRD4 degrader MZ1 can induce protein-protein interactions with the E3 ligase leading to more stable and cooperative ternary complexes for BRD4 over other BET bromodomains. 19 While designing selective small-molecule inhibitors for class I bromodomains remains challenging, 20 forming distinct ternary complexes is a potential alternative for targeting specific members of the family. Targeted protein degradation may also be a useful therapeutic tool given that it allows the full protein to be removed through sub-stoichiometric treatment of degrader compounds in an event-driven process.…”