PUBLICATION

Ventromorphins: A new class of small molecule activators of the canonical BMP signaling pathway

Authors
Genthe, J.R., Min, J., Farmer, D.M., Shelat, A.A., Grenet, J.A., Lin, W., Finkelstein, D.B., Vrijens, K., Chen, T., Guy, R.K., Clements, W.K., Roussel, M.F.
ID
ZDB-PUB-170809-3
Date
2017
Source
ACS Chemical Biology   12(9): 2436-2447 (Journal)
Registered Authors
Clements, Wilson, Genthe, Jamie
Keywords
none
MeSH Terms
  • Animals
  • Bone Morphogenetic Proteins/agonists*
  • Bone Morphogenetic Proteins/metabolism*
  • Cell Differentiation/drug effects*
  • Cell Line
  • Cell Line, Tumor
  • Chalcones/pharmacology
  • Drug Discovery
  • Gene Expression Profiling
  • Gene Expression Regulation/drug effects
  • Humans
  • Mice
  • Myoblasts/cytology
  • Myoblasts/drug effects
  • Myoblasts/metabolism
  • Osteoblasts/cytology
  • Osteoblasts/drug effects
  • Osteoblasts/metabolism
  • Osteogenesis/drug effects
  • Signal Transduction/drug effects*
  • Smad Proteins/metabolism
  • Small Molecule Libraries/chemistry
  • Small Molecule Libraries/pharmacology*
  • Zebrafish/embryology
PubMed
28787124 Full text @ ACS Chem. Biol.
Abstract
Here we describe three new small-molecule activators of BMP signaling found by high throughput screening of a library of ~600,000 small molecules. Using a cell-based luciferase assay in the BMP-4-responsive human cervical carcinoma clonal cell line, C33A-2D2, we identified three compounds with similar chemotypes that each ventralize zebrafish embryos and stimulate increased expression of the BMP target genes, bmp2b and szl. Because these compounds ventralize zebrafish embryos, we have termed them "ventromorphins." As expected for a BMP pathway activator, they induce the differentiation of C2C12 myoblasts to osteoblasts. Affymetrix RNA analysis confirmed the differentiation results and showed that ventromorphin treatment elicits a genetic response similar to BMP-4 treatment. Unlike Isoliquiritigenin (SJ000286237), a flavone that maximally activates the pathway after 24 hours of treatment, all three ventromorphins induced SMAD1/5/8 phosphorylation within 30 minutes of treatment and achieved peak activity within 1 hour, indicating that their responses are consistent with directly activating BMP signaling.
Errata / Notes
This article is corrected by ZDB-PUB-220906-159 .
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping