Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

• Published in: ACS chemical biology Vol. 10; no. 8; pp. 1770 - 1777
• Main Authors: Zengerle, Michael, Chan, Kwok-Ho, Ciulli, Alessio
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.08.2015
• Subjects: Cell Cycle Proteins; Dipeptides - chemistry; Dipeptides - pharmacology; Drug Design; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Letters; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Nuclear Proteins - metabolism; Proteolysis - drug effects; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Transcription Factors - metabolism; Ubiquitin-Protein Ligases - metabolism; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.5b00216

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 activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.