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 BMP pathway activators, they induce the differentiation of C2C12 myoblasts to osteoblasts. Affymetrix RNA analysis confirmed the differentiation results and showed that ventromorphins treatment elicits a response similar to BMP4 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 activated BMP signaling.

Addition of Chk1 inhibitor and BMP4 cooperatively promotes retinal tissue formation in self-organizing human pluripotent stem cell differentiation culture

“…We first investigated whether a small molecule can enhance retinal differentiation either alone or in combination with rhBMP4. We examined the effect of three candidate BMP signal activators at two concentrations; SB-4 [ 25 ], SJ000286237 [ 26 ] and PD407824 (PD) [ 23 ]. Using hESC line (KhES-1) with V enus cDNA knocked in the locus of the retinal progenitor marker Rx [ 27 ], we evaluated retinal differentiation by the induction of Rx:: Venus expression, following a self-organizing retinal differentiation protocol SFEBq with some modifications that used preconditioning and BMP4 methods ( Fig.…”

Oxysterols as promising small molecules for bone tissue engineering: Systematic review

“…It is likely that this literature will continue to expand, as high-throughput screening allows for the concomitant testing of thousands of compounds, accelerating the identification of osteogenic compounds[ 45 , 49 , 50 ]. To exemplify this, Genthe et al[ 51 ] recently used high-throughput screening of a library of approximately 600000 small molecules to identify a new class of osteogenic small molecules, called “ventromorphins”. These previously undescribed agents were found to directly activate BMP signaling[ 51 ].…”

“…To exemplify this, Genthe et al[ 51 ] recently used high-throughput screening of a library of approximately 600000 small molecules to identify a new class of osteogenic small molecules, called “ventromorphins”. These previously undescribed agents were found to directly activate BMP signaling[ 51 ]. Other groups around the world have used similar techniques to identify promising small molecules for bone tissue engineering across a wide-range of drug classes[ 50 , 52 - 55 ].…”

Optogenetic Control of the BMP Signaling Pathway

“… 5 − 9 However, control of the BMP signaling pathway is primarily limited to the use of inconsistent and costly recombinant growth factors; with synthetic small molecules not yet considered potent enough for tissue engineering approaches. 10 …”