Identification of Small Molecule Activators of BMP Signaling
- Authors
- Vrijens, K., Lin, W., Cui, J., Farmer, D., Low, J., Pronier, E., Zeng, F.Y., Shelat, A.A., Guy, K., Taylor, M.R., Chen, T., and Roussel, M.F.
- ID
- ZDB-PUB-130410-4
- Date
- 2013
- Source
- PLoS One 8(3): e59045 (Journal)
- Registered Authors
- Taylor, Michael R.
- Keywords
- none
- MeSH Terms
-
- Animals
- Bone Morphogenetic Proteins/agonists*
- Bone Morphogenetic Proteins/metabolism*
- Cell Line, Tumor
- Chalcone/pharmacology
- Drug Discovery*
- Embryo, Nonmammalian/drug effects
- Embryonic Development/drug effects
- Flavones/pharmacology
- Genes, Reporter
- High-Throughput Screening Assays
- Humans
- Mice
- Mice, Knockout
- Myoblasts/cytology
- Myoblasts/drug effects
- Osteoblasts/cytology
- Osteoblasts/drug effects
- Signal Transduction/drug effects*
- Small Molecule Libraries*
- Zebrafish
- PubMed
- 23527084 Full text @ PLoS One
Bone Morphogenetic Proteins (BMPs) are morphogens that play a major role in regulating development and homeostasis. Although BMPs are used for the treatment of bone and kidney disorders, their clinical use is limited due to the supra-physiological doses required for therapeutic efficacy causing severe side effects. Because recombinant BMPs are expensive to produce, small molecule activators of BMP signaling would be a cost-effective alternative with the added benefit of being potentially more easily deliverable. Here, we report our efforts to identify small molecule activators of BMP signaling. We have developed a cell-based assay to monitor BMP signaling by stably transfecting a BMP-responsive human cervical carcinoma cell line (C33A) with a reporter construct in which the expression of luciferase is driven by a multimerized BMP-responsive element from the Id1 promoter. A BMP-responsive clone C33A-2D2 was used to screen a bioactive library containing ~5,600 small molecules. We identified four small molecules of the family of flavonoids all of which induced luciferase activity in a dose-dependent manner and ventralized zebrafish embryos. Two of the identified compounds induced Smad1, 5 phosphorylation (P-Smad), Id1 and Id2 expression in a dose-dependent manner demonstrating that our assays identified small molecule activators of BMP signaling.