The experimental power of FR900359 to study Gq-regulated biological processes PMID: 26658454

ADC Targets in Oncology

2026-04-10

The experimental power of FR900359 to study Gq-regulated biological processes

Nat Commun. 2015 Dec 14;6:10156. doi: 10.1038/ncomms10156.

Ramona Schrage ¹ ² , Anna-Lena Schmitz ¹ , Evelyn Gaffal ³ , Suvi Annala ¹ , Stefan Kehraus ⁴ , Daniela Wenzel ⁵ , Katrin M Büllesbach ¹ , Tobias Bald ³ , Asuka Inoue ⁶ ⁷ , Yuji Shinjo ⁶ , Ségolène Galandrin ⁸ , Naveen Shridhar ³ , Michael Hesse ⁵ , Manuel Grundmann ¹ , Nicole Merten ¹ , Thomas H Charpentier ⁹ , Matthew Martz ¹⁰ , Adrian J Butcher ¹¹ , Tanja Slodczyk ³ , Sylvain Armando ¹² , Maike Effern ¹³ , Yoon Namkung ¹² , Laura Jenkins ¹⁴ , Velten Horn ¹⁵ , Anne Stößel ¹⁶ , Harald Dargatz ¹ , Daniel Tietze ¹⁵ , Diana Imhof ¹⁷ , Céline Galés ⁸ , Christel Drewke ¹ , Christa E Müller ¹⁶ , Michael Hölzel ¹³ , Graeme Milligan ¹⁴ , Andrew B Tobin ¹¹ , Jesús Gomeza ¹ , Henrik G Dohlman ¹⁰ , John Sondek ⁹ , T Kendall Harden ⁹ , Michel Bouvier ¹⁸ , Stéphane A Laporte ¹² , Junken Aoki ⁶ ¹⁹ , Bernd K Fleischmann ⁵ , Klaus Mohr ² , Gabriele M König ⁴ , Thomas Tüting ³ , Evi Kostenis ¹

Affiliations

1. Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
2. Pharmacology &Toxicology Section, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany.
3. Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, 53105 Bonn, Germany.
4. Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
5. Institute of Physiology I, Life and Brain Center, University of Bonn, 53105 Bonn, Germany.
6. Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai City 980-0065, Japan.
7. Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
8. Institut des Maladies Métaboliques et Cardiovasculaires, Institut Nataional de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, 31432 Toulouse, France.
9. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
10. Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
11. Medical Research Council Toxicology Unit, University of Leicester, Hodgkin building, Leicester LE1 9HN, UK.
12. Department of Medicine, McGill University, and the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H4A 3J1.
13. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
14. Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland G12 8QQ, UK.
15. Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
16. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany.
17. Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany.
18. Department of Biochemistry and Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Québec, Canada QC H3C IJ4.
19. Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan.

Abstract

Despite the discovery of heterotrimeric αβγ G proteins ∼25 years ago, their selective perturbation by cell-permeable inhibitors remains a fundamental challenge. Here we report that the plant-derived depsipeptide FR900359 (FR) is ideally suited to this task. Using a multifaceted approach we systematically characterize FR as a selective inhibitor of Gq/11/14 over all Other mammalian Gα isoforms and elaborate its molecular mechanism of action. We also use FR to investigate whether inhibition of Gq proteins is an effective post-receptor strategy to target oncogenic signalling, using melanoma as a model system. FR suppresses many of the hallmark features that are central to the malignancy of melanoma cells, thereby providing new opportunities for therapeutic intervention. Just as pertussis toxin is used extensively to probe and inhibit the signalling of Gi/o proteins, we anticipate that FR will at least be its equivalent for investigating the biological relevance of Gq.