Ventromorphins: A New Class of Small Molecule Activators of the Canonical BMP Signaling Pathway

ACS Chem Biol. 2017 Sep 15;12(9):2436-2447. doi: 10.1021/acschembio.7b00527. Epub 2017 Aug 29.


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 BMP4-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 ventromorphins treatment elicits a genetic response similar to BMP4 treatment. Unlike isoliquiritigenin (SJ000286237), a flavone that maximally activates the pathway after 24 h of treatment, all three ventromorphins induced SMAD1/5/8 phosphorylation within 30 min of treatment and achieved peak activity within 1 h, indicating that their responses are consistent with directly activating BMP signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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


  • Bone Morphogenetic Proteins
  • Chalcones
  • Smad Proteins
  • Small Molecule Libraries
  • isoliquiritigenin