PUBLICATION
Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin
- Authors
- Li, S., Ai, N., Shen, M., Dang, Y., Chong, C.M., Pan, P., Kwan, Y.W., Chan, S.W., Leung, G.P.H., Hoi, M.P.M., Hou, T., Lee, S.M.
- ID
- ZDB-PUB-170829-2
- Date
- 2017
- Source
- Cell death discovery 3: 17051 (Journal)
- Registered Authors
- Keywords
- Drug development, Virtual screening
- MeSH Terms
- none
- PubMed
- 28845297 Full text @ Cell Death Discov
Citation
Li, S., Ai, N., Shen, M., Dang, Y., Chong, C.M., Pan, P., Kwan, Y.W., Chan, S.W., Leung, G.P.H., Hoi, M.P.M., Hou, T., Lee, S.M. (2017) Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin. Cell death discovery. 3:17051.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping