Identification of a novel function of CX-4945 as a splicing regulator = CX-4945의 스플라이싱 조절기능 규명

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Title
Identification of a novel function of CX-4945 as a splicing regulator = CX-4945의 스플라이싱 조절기능 규명
Author(s)
Hyeongki Kim; Kwangman Choi; Hyunju Kang; S Y Lee; Seung-Wook Chi; Min-Sung Lee; J Song; Donghwa Im; Y Choi; Sungchan Cho
Bibliographic Citation
PLoS One, vol. 9, no. 4, pp. e94978-e94978
Publication Year
2014
Abstract
Alternative splicing is a nearly ubiquitous versatile process that controls gene expression and creates numerous protein isoforms with different functions from a single gene. The significance of alternative splicing has been confirmed by the increasing number of human diseases that are caused by misregulation of splicing events. Very few compounds, however, have been reported to act as inhibitors of alternative splicing, and their potential clinical use needs to be evaluated. Here, we report that CX-4945, a previously well-characterized inhibitor of casein kinase 2 (CK2) and a molecule currently in clinical trials (Phase II) for cancer treatment, regulates splicing in mammalian cells in a CK2-independent manner. Transcriptomewide analysis using exon array also showed a widespread alteration in alternative splicing of numerous genes. We found that CX-4945 potently inhibits the Cdc2-like kinases (Clks) in vitro and in turn, leads to suppression of the phosphorylation of serine/arginine-rich (SR) proteins in mammalian cells. Surprisingly, the overall efficacy of CX-4945 on Clks (IC50 = 390 nM) was stronger than that of TG-003, the strongest inhibitor reported to date. Of the Clks, Clk2 was most strongly inhibited by CX-4945 in an ATP-competitive manner. Our research revealed an unexpected activity of the drug candidate CX-4945 as a potent splicing modulator and also suggested a potential application for therapy of diseases caused by abnormal splicing.
ISSN
1932-6203
Publisher
Public Library of Science
DOI
http://dx.doi.org/10.1371/journal.pone.0094978
Type
Article
Appears in Collections:
Division of Biomedical Research > 1. Journal Articles
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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