Identification of small molecule activators of BMP signaling

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 seve...

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Bibliographic Details
Published in:PloS one 2013-03, Vol.8 (3), p.e59045
Main Authors: Vrijens, Karen, Lin, Wenwei, Cui, Jimmy, Farmer, Dana, Low, Jonathan, Pronier, Elodie, Zeng, Fu-Yue, Shelat, Anang A, Guy, Kiplin, Taylor, Michael R, Chen, Taosheng, Roussel, Martine F
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biology
Bone morphogenetic proteins
Bone Morphogenetic Proteins - agonists
Bone Morphogenetic Proteins - metabolism
Cell Line, Tumor
Cell signaling
Cervical cancer
Cervical carcinoma
Cervix
Chalcone - pharmacology
Children & youth
Danio rerio
Drug Discovery
Embryo, Nonmammalian - drug effects
Embryonic development
Embryonic Development - drug effects
Embryos
Flavones - pharmacology
Flavonoids
Genes, Reporter
Health aspects
High-Throughput Screening Assays
Homeostasis
Human behavior
Humans
Id1 protein
Isoflavones
Kinases
Laboratory animals
Medical screening
Mice
Mice, Knockout
Mutation
Myoblasts - cytology
Myoblasts - drug effects
Osteoblasts - cytology
Osteoblasts - drug effects
Phosphorylation
Physiological effects
Proteins
Pulmonary arteries
Regulatory sequences
Side effects
Signal Transduction - drug effects
Signaling
Smad protein
Small Molecule Libraries
Zebrafish
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0059045