Please use this identifier to cite or link to this item:
http://hdl.handle.net/10397/88814
Title: | Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin | Authors: | Li, S Ai, NN Shen, MY Dang, YY Chong, CM Pan, PC Kwan, YW Chan, SW Leung, GPH Hoi, MPM Hou, TJ Lee, SMY |
Issue Date: | 2017 | Source: | Cell death discovery, 2017, , v. 3, 17051, p. 1-11 | Abstract: | Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and no therapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for hemorrhagic stroke. ROCKS, which belong to the serine/threonine protein kinase family and participate in the organization of actin cytoskeleton, have become attractive targets for the treatment of strokes. In this study, in vitro enzyme-based assays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibit ROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1, and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions. Furthermore, FPND significantly prevented statin-induced cerebral hemorrhage in a zebrafish model. In addition, in vitro studies using the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented statin-induced cerebral hemorrhage by enhancing endothelial cell-cell junctions through inhibiting the ROCK-mediated VE-cadherin signaling pathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrity loss-related diseases, such as hemorrhagic stroke. | Publisher: | Nature Publishing Group | Journal: | Cell death discovery | EISSN: | 2058-7716 | DOI: | 10.1038/cddiscovery.2017.51 | Rights: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ The following publication Li, S., Ai, N., Shen, M. et al. Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin. Cell Death Discov. 3, 17051 (2017) is available at https://dx.doi.org/10.1038/cddiscovery.2017.51 |
Appears in Collections: | Journal/Magazine Article |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Li_Discovery_Rock_Inhibitor.pdf | 4.13 MB | Adobe PDF | View/Open |
Page views
45
Last Week
0
0
Last month
Citations as of May 5, 2024
Downloads
16
Citations as of May 5, 2024
SCOPUSTM
Citations
16
Citations as of Apr 26, 2024
WEB OF SCIENCETM
Citations
16
Citations as of May 2, 2024
Google ScholarTM
Check
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.