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Chem Biol. 2015 Jun 18;22(6):755-63. doi: 10.1016/j.chembiol.2015.05.009. Epub 2015 Jun 4.

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.

Author information

1
Arvinas, Inc., New Haven, CT 06511, USA.
2
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
3
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA; Department of Chemistry, Yale University, New Haven, CT 06511, USA; Department of Pharmacology, Yale University, New Haven, CT 06511, USA. Electronic address: craig.crews@yale.edu.

Abstract

BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.

PMID:
26051217
PMCID:
PMC4475452
DOI:
10.1016/j.chembiol.2015.05.009
[Indexed for MEDLINE]
Free PMC Article

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