A High-Content Screen Reveals New Small-Molecule Enhancers of Ras/Mapk Signaling as Probes for Zebrafish Heart Development

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Manush SaydmohammedMichael Tsang

Abstract

Zebrafish is the preferred vertebrate model for high throughput chemical screens to discover modulators of complex biological pathways. We adapted a transgenic zebrafish line, Tg(dusp6:EGFP), which reports on fibroblast growth factor (Fgf)/Ras/Mapk activity, into a quantitative, high-content chemical screen to identify novel Fgf hyperactivators as chemical probes for zebrafish heart development and regeneration. We screened 10,000 compounds from the TimTec ActiProbe library, and identified several structurally distinct classes of molecules that enhanced Fgf/Ras/Mapk signaling. We chose three agents-ST020101, ST011282, and ST006994-for confirmatory and functional studies based on potency, repeatability with repurchased material, favorable whole organism toxicity, and evidence of structure⁻activity relationships. Functional follow-up assays confirmed that all three compounds induced the expression of Fgf target genes during zebrafish embryonic development. Moreover, these compounds increased cardiac progenitor populations by effecting a fate change from endothelial to cardiac progenitors that translated into increased numbers of cardiomyocytes. Interestingly, ST006994 augmented Fgf/Ras/Mapk signaling without increasing Erk phosph...Continue Reading

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Citations

Jan 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jóhannes Reynisson
Jun 11, 2019·Frontiers in Pharmacology·Nils OhnesorgeBreandán N Kennedy
Aug 17, 2020·Journal of Virology·Xiaofan LiSumita Bhaduri-McIntosh
Mar 12, 2021·Cardiovascular Research·Fabian Philipp KreutzerThomas Thum

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Methods Mentioned

BETA
transgenic
electrophoretic light scattering

Software Mentioned

Imaris
Cellenger
Image
TimTec
PAINS
Studio
Mapk
GraphPad Prism
Badapple

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