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Title: Stereospecific inhibitory effects of CCG-1423 on the cellular events mediated by myocardin-related transcription factor A
Authors: Watanabe, Bunta  kyouindb  KAKEN_id  orcid (unconfirmed)
Minami, Saki
Ishida, Hideaki
Yoshioka, Ryuzo
Nakagawa, Yoshiaki
Morita, Tsuyoshi
Hayashi, Ken'Ichiro
Author's alias: 渡辺, 文太
中川, 好秋
Issue Date: 21-Aug-2015
Publisher: Public Library of Science
Journal title: PLOS ONE
Volume: 10
Issue: 8
Thesis number: e0136242
Abstract: CCG-1423 suppresses several pathological processes including cancer cell migration, tissue fibrosis, and the development of atherosclerotic lesions. These suppressions are caused by inhibition of myocardin-related transcription factor A (MRTF-A), which is a critical factor for epithelial-mesenchymal transition (EMT). CCG-1423 can therefore be a potent inhibitor for EMT. CCG-1423 and related compounds, CCG-100602 and CCG-203971 possess similar biological activities. Although these compounds are comprised of two stereoisomers, the differences in their biological activities remain to be assessed. To address this issue, we stereoselectively synthesized optically pure isomers of these compounds and validated their biological activities. The S-isomer of CCG-1423 rather than the R-isomer exhibited modestly but significantly higher inhibitory effects on the cellular events triggered by MRTF-A activation including serum response factor-mediated gene expression and cell migration of fibroblasts and B16F10 melanoma cells. Accordingly, the S-isomer of CCG- 1423 more potently blocked the serum-induced nuclear import of MRTF-A than the R-isomer. No such difference was observed in cells treated with each of two stereoisomers of CCG-100602 or CCG-203971. We previously reported that the N-terminal basic domain (NB), which functions as a nuclear localization signal of MRTF-A, is a binding site for CCG- 1423. Consistent with the biological activities of two stereoisomers of CCG-1423, docking simulation demonstrated that the S-isomer of CCG-1423 was more likely to bind to NB than the R-isomer. This is a first report demonstrating the stereospecific biological activities of CCG-1423.
Rights: © 2015 Watanabe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
DOI(Published Version): 10.1371/journal.pone.0136242
PubMed ID: 26295164
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