Proteolysis targeting chimeras (PROTACs) are chimeric small molecules designed to bind both a target protein and an E3 ligase to mediate ubiquitination of the target protein and its subsequent degradation via the ubiquitin proteasome system (UPS). Our recent successes in identifying PROTACs that recruit cereblon (CRBN) and von Hippel Lindau (VHL) E3 ligases to potently degrade BRD4, a well described epigenetics cancer target, in vitro and in vivo will be described. Unlike BRD4 antagonists, BRD4 PROTAC degraders demonstrated significantly higher effect in c-Myc suppression, proliferation inhibition and apoptosis induction. In a castration resistant prostate cancer (CRPC) mouse xenograft model, BRD4 degraders demonstrated dose dependent knock down of the BRD4 protein and tumor regression. These data suggest degrading BRD4 could potentially represent an important therapeutic advance in the treatment of CRPC.

Hijacking ubiquitin E3 ligases using PROTAC technology to effectively degrade BRD4 and achieve anti-tumor efficacy

251st National Meeting (2016)

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