title: Identification of small molecule activators of BMP signaling.
abstract: 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.
authors.affiliation: Departments of Tumor Cell Biology, Memphis, Tennessee, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Vrijens
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.forename: Jimmy
authors.initials: J
authors.lastname: Cui
authors.forename: Dana
authors.initials: D
authors.lastname: Farmer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Low
authors.forename: Elodie
authors.initials: E
authors.lastname: Pronier
authors.forename: Fu-Yue
authors.initials: FY
authors.lastname: Zeng
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: Kiplin
authors.initials: K
authors.lastname: Guy
authors.forename: Michael R
authors.initials: MR
authors.lastname: Taylor
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000819:agonists* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002599:Chalcone / Q000494:pharmacology; D055808:Drug Discovery; D004625:Embryo, Nonmammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D047309:Flavones / Q000494:pharmacology; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries; D015027:Zebrafish
chemical_list: D019485:Bone Morphogenetic Proteins; D047309:Flavones; D054852:Small Molecule Libraries; D002599:Chalcone