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

Jamie R. Genthe; Jaeki Min; Dana M. Farmer; Anang A. Shelat; Jose A. Grenet; Wenwei Lin; David Finkelstein; Karen Vrijens; Taosheng Chen; R. Kiplin Guy; Wilson K. Clements; Martine F. Roussel

doi:10.1021/acschembio.7b00527

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

Jamie R. Genthe, Jaeki Min, Dana M. Farmer, Anang A. Shelat, Jose A. Grenet, Wenwei Lin, David Finkelstein, Karen Vrijens, Taosheng Chen, R. Kiplin Guy, Wilson K. Clements, Martine F. Roussel

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19 Scopus citations

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 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.

Original language	English
Pages (from-to)	2436-2447
Number of pages	12
Journal	ACS Chemical Biology
Volume	12
Issue number	9
DOIs	https://doi.org/10.1021/acschembio.7b00527
State	Published - Sep 15 2017

Bibliographical note

Funding Information:
Conception, experimental design, and direction of the work (M.F.R., R.K.G., W.K.C.); writing of the manuscript (M.F.R., J.R.G., J.M., W.K.C.); high throughput screen (J.M., A.A.S., W.L., T.C., K.V.); zebrafish experiments (J.R.G.), immunoblotting (D.M.F., J.A.G.); other cell-based experiments (J.R.G., D.M.F., J.A.G.); analysis of the Affymetrix database (D.F.). All authors have read the manuscript. Funding This work was funded in part by NCI grant CA096832 (MFR), Core Grant CA-02165 (M.F.R.), James McDonnell Foundation−Brain Cancer Research Award (M.F.R.), St. Jude Cancer Center Grant P30CA021765 (M.F.R., T.C.), AACR-Astellas USA Foundation Fellowship in Basic Cancer Research (K.V.), American Brain Tumor Association fellowship (K.V.), March of Dimes Basil O’Connor Starter Scholar Award #5-FY-14 (W.K.C.), St. Jude Cancer Center Grant P30CA021765 (W.K.C.), and the American−Lebanese Syrian-Associated Charities of St. Jude Children’s Research Hospital. Notes The authors declare no competing financial interest. #These authors share senior authorship.

Publisher Copyright:
© 2017 American Chemical Society.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/acschembio.7b00527

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@article{59c6a9f63c7740af8d4d7dffaa0e84a1,

title = "Ventromorphins: A New Class of Small Molecule Activators of the Canonical BMP Signaling Pathway",

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 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.",

author = "Genthe, {Jamie R.} and Jaeki Min and Farmer, {Dana M.} and Shelat, {Anang A.} and Grenet, {Jose A.} and Wenwei Lin and David Finkelstein and Karen Vrijens and Taosheng Chen and Guy, {R. Kiplin} and Clements, {Wilson K.} and Roussel, {Martine F.}",

note = "Funding Information: Conception, experimental design, and direction of the work (M.F.R., R.K.G., W.K.C.); writing of the manuscript (M.F.R., J.R.G., J.M., W.K.C.); high throughput screen (J.M., A.A.S., W.L., T.C., K.V.); zebrafish experiments (J.R.G.), immunoblotting (D.M.F., J.A.G.); other cell-based experiments (J.R.G., D.M.F., J.A.G.); analysis of the Affymetrix database (D.F.). All authors have read the manuscript. Funding This work was funded in part by NCI grant CA096832 (MFR), Core Grant CA-02165 (M.F.R.), James McDonnell Foundation−Brain Cancer Research Award (M.F.R.), St. Jude Cancer Center Grant P30CA021765 (M.F.R., T.C.), AACR-Astellas USA Foundation Fellowship in Basic Cancer Research (K.V.), American Brain Tumor Association fellowship (K.V.), March of Dimes Basil O{\textquoteright}Connor Starter Scholar Award #5-FY-14 (W.K.C.), St. Jude Cancer Center Grant P30CA021765 (W.K.C.), and the American−Lebanese Syrian-Associated Charities of St. Jude Children{\textquoteright}s Research Hospital. Notes The authors declare no competing financial interest. #These authors share senior authorship. Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

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doi = "10.1021/acschembio.7b00527",

language = "English",

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T2 - A New Class of Small Molecule Activators of the Canonical BMP Signaling Pathway

AU - Genthe, Jamie R.

AU - Min, Jaeki

AU - Farmer, Dana M.

AU - Shelat, Anang A.

AU - Grenet, Jose A.

AU - Lin, Wenwei

AU - Finkelstein, David

AU - Vrijens, Karen

AU - Chen, Taosheng

AU - Guy, R. Kiplin

AU - Clements, Wilson K.

AU - Roussel, Martine F.

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PY - 2017/9/15

Y1 - 2017/9/15

N2 - 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.

AB - 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.

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

Abstract

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