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