title: Stereospecific Inhibitory Effects of CCG-1423 on the Cellular Events Mediated by Myocardin-Related Transcription Factor A.
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.
authors: Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan.
authors: Bunta
authors: B
authors: Watanabe
authors: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.
authors: Saki
authors: S
authors: Minami
authors: Toabo Corporation Co., Ltd., Crystal Tower 18F, 2-27, 1-Chome, Shiromi, Chuo-ku, Osaka, 540-6018, Japan.
authors: Hideaki
authors: H
authors: Ishida
authors: NAHLS Co., Ltd., Room 2203, Kyodai Katsura Venture Plaza South Building, 1-39 Goryo-Ohara, Nishikyo-ku, Kyoto, 615-8245, Japan.
authors: Ryuzo
authors: R
authors: Yoshioka
authors: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.
authors: Yoshiaki
authors: Y
authors: Nakagawa
authors: Department of RNA Biology and Neuroscience, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors: Tsuyoshi
authors: T
authors: Morita
authors: Department of RNA Biology and Neuroscience, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors: Ken'ichiro
authors: K
authors: Hayashi
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D062105:Molecular Docking Simulation; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D041681:NIH 3T3 Cells; D061251:Primary Cell Culture; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000813:Anilides; D001549:Benzamides; C523455:CCG 1423; C431575:MRTFA protein, human; D015534:Trans-Activators