Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The…

• UO
  University of Dundee
• WT
  Wellcome Trust

  Awards: 097945/Z/11/Z, 097945
• DF
  Directorate for Biological Sciences
• MR
  Medical Research Council
• BA
  Biotechnology and Biological Sciences Research Council

  Awards: BB/J001201/1, BB/J001201/2, BB/G023123/2, G023123/2, BB/J001201/2, BB/G023123/2
• ER
  European Research Council

  Award: 311460