Journal
ACS CHEMICAL BIOLOGY
Volume 12, Issue 9, Pages 2436-2447Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.7b00527
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Funding
- NCI [CA096832, CA-02165]
- James McDonnell Foundation
- St. Jude Cancer Center [P30CA021765]
- AACR-Astellas USA Foundation
- American Brain Tumor Association
- March of Dimes Basil O'Connor Starter Scholar Award [5-FY-14]
- American Lebanese Syrian-Associated Charities of St. Jude Children's Research Hospital
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Here, we describe three new small-molecule activators of BMP signaling found by high throughput screening of a library of similar to 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.
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