CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model

Natsuki Imayoshi; Makoto Yoshioka; Jay Chauhan; Susumu Nakata; Yuki Toda; Steven Fletcher; Jeffrey W Strovel; Kazuyuki Takata; Eishi Ashihara

doi:10.1016/j.bbrc.2017.01.088

CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model

Biochem Biophys Res Commun. 2017 Mar 4;484(2):262-268. doi: 10.1016/j.bbrc.2017.01.088. Epub 2017 Jan 20.

Authors

Natsuki Imayoshi¹, Makoto Yoshioka², Jay Chauhan³, Susumu Nakata⁴, Yuki Toda¹, Steven Fletcher³, Jeffrey W Strovel², Kazuyuki Takata¹, Eishi Ashihara⁵

Affiliations

¹ Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
² ConverGene LLC, Gaithersburg, MD, USA.
³ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.
⁴ Department of Clinical Oncology, Kyoto Pharmaceutical University, Kyoto, Japan.
⁵ Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan. Electronic address: ash@mb.kyoto-phu.ac.jp.

PMID: 28115161
DOI: 10.1016/j.bbrc.2017.01.088

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 IC₅₀ value 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.

Keywords: Bromodomain; Multiple myeloma; Orthotopic mouse model; c-myc.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects*
Disease Models, Animal*
Enhancer Elements, Genetic
Genes, myc
Humans
Mice
Multiple Myeloma / genetics
Multiple Myeloma / pathology*
Nuclear Proteins / antagonists & inhibitors*
Promoter Regions, Genetic
Quinolones / pharmacology*
Survival Analysis
Transcription Factors / antagonists & inhibitors*

Substances

Brd4 protein, mouse
Nuclear Proteins
Quinolones
Transcription Factors