title: BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
abstract: MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors: Jake E
authors: JE
authors: Delmore
authors: Ghayas C
authors: GC
authors: Issa
authors: Madeleine E
authors: ME
authors: Lemieux
authors: Peter B
authors: PB
authors: Rahl
authors: Junwei
authors: J
authors: Shi
authors: Hannah M
authors: HM
authors: Jacobs
authors: Efstathios
authors: E
authors: Kastritis
authors: Timothy
authors: T
authors: Gilpatrick
authors: Ronald M
authors: RM
authors: Paranal
authors: Jun
authors: J
authors: Qi
authors: Marta
authors: M
authors: Chesi
authors: Anna C
authors: AC
authors: Schinzel
authors: Michael R
authors: MR
authors: McKeown
authors: Timothy P
authors: TP
authors: Heffernan
authors: Christopher R
authors: CR
authors: Vakoc
authors: P Leif
authors: PL
authors: Bergsagel
authors: Irene M
authors: IM
authors: Ghobrial
authors: Paul G
authors: PG
authors: Richardson
authors: Richard A
authors: RA
authors: Young
authors: William C
authors: WC
authors: Hahn
authors: Kenneth C
authors: KC
authors: Anderson
authors: Andrew L
authors: AL
authors: Kung
authors: James E
authors: JE
authors: Bradner
authors: Constantine S
authors: CS
authors: Mitsiades
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; D001569:Benzodiazepines; C554645:molibresib