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Discovery of a novel ROCK2 inhibitor with anti-migration effects via docking and high-content drug screening
Cheong-Meng Chong1; Man-Teng Kou1; Peichen Pan2; Hefeng Zhou1; Nana Ai1; Chuwen Li1; Hai-Jing Zhong1; Chung-Hang Leung1; Tingjun Hou2,3; Simon Ming-Yuen Lee1
2016
Source PublicationMOLECULAR BIOSYSTEMS
ISSN1742-206X
Volume12Issue:9Pages:2713-2721
Abstract

Rho-associated protein kinase (ROCK) mediated the reorganization of the actin cytoskeleton and has been implicated in the spread and metastatic process of cancer. In this study, structure-based high-throughput virtual screening was used to identify candidate compounds targeting ROCK2 from a chemical library. Moreover, high-content screening based on neurite outgrowth of SH-SY5Y cells (a human neuroblastoma cell line) was used for accelerating the identification of compounds with characteristics of ROCK2 inhibitors. The effects of bioactive ROCK2 inhibitor candidates were further validated using other bioassays including cell migration and wound healing in SH-SY5Y cells. Through the combined virtual and high-content drug screening, the compound 1,3-benzodioxol-5-yl[1-(5-isoquinolinylmethyl)-3-piperidinyl]-methanone (BIPM) was identified as a novel and potent ROCK2 inhibitor. Exposure of SH-SY5Y cells to BIPM led to significant changes in neurite length, cell migration and actin stress fibers. Further experiments demonstrated that BIPM was able to significantly inhibit phosphorylation of cofilin, a regulatory protein of actin cytoskeleton. These results suggest that BIPM could be considered as a promising scaffold for the further development of ROCK2 inhibitors for anti-cancer metastasis.

DOI10.1039/c6mb00343e
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000382253100005
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorTingjun Hou; Simon Ming-Yuen Lee
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, and Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
3.Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Cheong-Meng Chong,Man-Teng Kou,Peichen Pan,et al. Discovery of a novel ROCK2 inhibitor with anti-migration effects via docking and high-content drug screening[J]. MOLECULAR BIOSYSTEMS,2016,12(9):2713-2721.
APA Cheong-Meng Chong.,Man-Teng Kou.,Peichen Pan.,Hefeng Zhou.,Nana Ai.,...&Simon Ming-Yuen Lee.(2016).Discovery of a novel ROCK2 inhibitor with anti-migration effects via docking and high-content drug screening.MOLECULAR BIOSYSTEMS,12(9),2713-2721.
MLA Cheong-Meng Chong,et al."Discovery of a novel ROCK2 inhibitor with anti-migration effects via docking and high-content drug screening".MOLECULAR BIOSYSTEMS 12.9(2016):2713-2721.
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