Structure-Guided Design of a “Bump-and-Hole” Bromodomain-Based Degradation Tag

Chemical
biology tools to modulate protein levels in cells are
critical to decipher complex biology. Targeted protein degradation
offers the potential for rapid and dose-dependent protein depletion
through the use of protein fusion tags toward which protein degraders
have been established. Here, we present a newly developed protein
degradation tag BRD4BD1L94V along with the corresponding
cereblon (CRBN)-based heterobifunctional degrader based on a “bump-and-hole”
approach. The resulting compound XY-06-007 shows a half-degradation
concentration (DC50, 6 h) of 10 nM against BRD4BD1L94V with no degradation of off-targets, as assessed by
whole proteome mass spectrometry, and demonstrates suitable pharmacokinetics
for in vivo studies. We demonstrate that BRD4BD1L94V can be combined with the dTAG approach to achieve simultaneous
degrader-mediated depletion of their respective protein fusions. This
orthogonal system complements currently available protein degradation
tags and enables investigation into the consequences resulting from
rapid degradation of previously undruggable disease codependencies.