PUBLICATION
In Vivo Structure Activity Relationship Study of Dorsomorphin Analogs Identifies Selective VEGF and BMP Inhibitors
- Authors
- Hao, J., Ho, J.N., Lewis, J.A., Karim, K.A., Daniels, R.N., Gentry, P.R., Hopkins, C., Lindsley, C., and Hong, C.C.
- ID
- ZDB-PUB-100105-3
- Date
- 2010
- Source
- ACS Chemical Biology 5(2): 245-253 (Journal)
- Registered Authors
- Hong, Charles
- Keywords
- none
- MeSH Terms
-
- Animals
- Bone Morphogenetic Proteins/antagonists & inhibitors*
- Drug Evaluation, Preclinical/methods
- Embryo, Nonmammalian/drug effects
- Pyrazoles/chemistry*
- Pyrazoles/pharmacology*
- Pyrimidines/chemistry*
- Pyrimidines/pharmacology*
- Quinolines/chemistry*
- Quinolines/pharmacology*
- Structure-Activity Relationship
- Vascular Endothelial Growth Factor A/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Zebrafish/embryology
- PubMed
- 20020776 Full text @ ACS Chem. Biol.
Citation
Hao, J., Ho, J.N., Lewis, J.A., Karim, K.A., Daniels, R.N., Gentry, P.R., Hopkins, C., Lindsley, C., and Hong, C.C. (2010) In Vivo Structure Activity Relationship Study of Dorsomorphin Analogs Identifies Selective VEGF and BMP Inhibitors. ACS Chemical Biology. 5(2):245-253.
Abstract
The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb zebrafish embryonic dorsoventral axis, we identified dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that dorsomorphin has significant "off-target" effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether dorsomorphin's anti-angiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogs that target BMP but not VEGF signaling, and vise versa. In a structure activity relationship (SAR) study of dorsomorphin analogs based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the BMP inhibitors, DMH1, which exclusively targets the BMP, but not VEGF, pathway, dorsalized the embryonic axis without disrupting angiogenic process, demonstrating that BMP signaling was not involved in angiogenic process. This is one of the first full-scale SAR study performed in vertebrates, and demonstrates the potential of zebrafish as an attractive complementary platform for drug development that incorporates an assessment of in vivo bioactivity and selectivity in the context of a living organism.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping