title: CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model.
abstract: Multiple myeloma (MM) is characterized by the clonal proliferation of neoplastic plasma cells. Despite a stream of new molecular targets based on better understanding of the disease, MM remains incurable. Epigenomic abnormalities contribute to the pathogenesis of MM. bromodomain 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, binds to acetylated histones during M/G1 transition in the cell cycle promoting progression to S phase. In this study, we investigated the effects of a novel BET inhibitor CG13250 on MM cells. CG13250 inhibited ligand binding to BRD4 in a dose-dependent manner and with an IC50value of 1.1 μM. It inhibited MM proliferation in a dose-dependent manner and arrested cells in G1, resulting in the induction of apoptosis through caspase activation. CG13250 inhibited the binding of BRD4 to c-MYC promoter regions suppressing the transcription of the c-MYC gene. Administered in vivo, CG13250 significantly prolonged survival of an orthotopic MM-bearing mice. In conclusion, CG13250 is a novel bromodomain inhibitor that is a promising molecular targeting agent against MM.
authors.affiliation: Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Imayoshi
authors.affiliation: ConverGene LLC, Gaithersburg, MD, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshioka
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Chauhan
authors.affiliation: Department of Clinical Oncology, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakata
authors.affiliation: Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Toda
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.affiliation: ConverGene LLC, Gaithersburg, MD, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Strovel
authors.affiliation: Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Takata
authors.affiliation: Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan. Electronic address: ash@mb.kyoto-phu.ac.jp.
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D016259:Genes, myc; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D015363:Quinolones / Q000494:pharmacology*; D016019:Survival Analysis; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D009687:Nuclear Proteins; D015363:Quinolones; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins
keywords: Bromodomain; Multiple myeloma; Orthotopic mouse model; c-myc