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Discovery of a novel ROCK2 inhibitor with anti-migration effects: Via docking and high-content drug screening
Chong C.-M.3; Kou M.-T.3; Pan P.1; Zhou H.3; Ai N.3; Li C.3; Zhong H.-J.3; Leung C.-H.3; Hou T.1; Lee S.M.-Y.3
2016-09-01
Source PublicationMolecular BioSystems
ISSN17422051 1742206X
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
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000382253100005
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被引频次[WOS]:3   [WOS记录]     [WOS相关记录]
Document TypeJournal article
专题Institute of Chinese Medical Sciences
Corresponding AuthorHou T.; Lee S.M.-Y.
Affiliation1.Zhejiang University
2.Soochow University
3.University of Macau
First Author AffilicationUniversity of Macau
Corresponding Author AffilicationUniversity of Macau
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Chong C.-M.,Kou M.-T.,Pan P.,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 Chong C.-M..,Kou M.-T..,Pan P..,Zhou H..,Ai N..,...&Lee S.M.-Y..(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 Chong C.-M.,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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