Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets

Mattias Kalén, Elisabet Wallgard, Noomi Asker, Aidas Nasevicius, Elisabet Athley, Erik Billgren, Jon D. Larson, Shannon A. Wadman, Elizabeth Norseng, Karl J Clark, Liqun He, Linda Karlsson-Lindahl, Ann Katrin Häger, Holger Weber, Hellmut Augustin, Tore Samuelsson, Chelsy K. Kemmet, Carly M. Utesch, Jeffrey J. Essner, Perry B. HackettMats Hellström

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

We combined reverse and chemical genetics to identify targets and compounds modulating blood vessel development. Through transcript profiling in mice, we identified 150 potentially druggable microvessel-enriched gene products. Orthologs of 50 of these were knocked down in a reverse genetic screen in zebrafish, demonstrating that 16 were necessary for developmental angiogenesis. In parallel, 1280 pharmacologically active compounds were screened in a human cell-based assay, identifying 28 compounds selectively inhibiting endothelial sprouting. Several links were revealed between the results of the reverse and chemical genetic screens, including the serine/threonine (S/T) phosphatases ppp1ca, ppp1cc, and ppp4c and an inhibitor of this gene family; Endothall. Our results suggest that the combination of reverse and chemical genetic screens, in vertebrates, is an efficient strategy for the identification of drug targets and compounds that modulate complex biological systems, such as angiogenesis.

Original languageEnglish (US)
Pages (from-to)432-441
Number of pages10
JournalChemistry and Biology
Volume16
Issue number4
DOIs
StatePublished - Apr 24 2009
Externally publishedYes

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Keywords

  • CELLBIO
  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Kalén, M., Wallgard, E., Asker, N., Nasevicius, A., Athley, E., Billgren, E., Larson, J. D., Wadman, S. A., Norseng, E., Clark, K. J., He, L., Karlsson-Lindahl, L., Häger, A. K., Weber, H., Augustin, H., Samuelsson, T., Kemmet, C. K., Utesch, C. M., Essner, J. J., ... Hellström, M. (2009). Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets. Chemistry and Biology, 16(4), 432-441. https://doi.org/10.1016/j.chembiol.2009.02.010