title: Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.
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.
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Altieri
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Hanqing
authors.initials: H
authors.lastname: Dong
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Kanak
authors.initials: K
authors.lastname: Raina
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hines
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Winkler
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Crew
authors.affiliation: Arvinas, Inc., New Haven, CT 06511, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Coleman
authors.affiliation: 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.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000083:Acetanilides / Q000633:toxicity; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000633:toxicity; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014230:Triazoles / Q000633:toxicity; D044767:Ubiquitin-Protein Ligases; D000092468:Bromodomain Containing Proteins
chemical_list: D000083:Acetanilides; D048868:Adaptor Proteins, Signal Transducing; D001381:Azepines; D018797:Cell Cycle Proteins; D006575:Heterocyclic Compounds, 3-Ring; D009687:Nuclear Proteins; D010447:Peptide Hydrolases; D016271:Proto-Oncogene Proteins c-myc; D013792:Thalidomide; D014157:Transcription Factors; D014230:Triazoles; D044767:Ubiquitin-Protein Ligases; C561695:(+)-JQ1 compound; C000606252:ARV-825; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C502543:CRBN protein, human; C000605331:OTX015