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Nature. 2014 Nov 20;515(7527):443-7. doi: 10.1038/nature13713. Epub 2014 Sep 14.

Discovery and characterization of small molecules that target the GTPase Ral.

Author information

1
Department of Surgery, University of Colorado, Aurora, Colorado 80045, USA.
2
Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
3
Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045, USA.
4
Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA.
5
Department of Pharmacology, University of Colorado, Aurora, Colorado 80045, USA.
6
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
7
1] Department of Cardiology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Cell Biology, Yale University, New Haven, Connecticut 06511, USA.
8
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA.
9
1] Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA [2] Department of Chemistry and Chemical Biology, Indiana University - Purdue University, Indianapolis, Indiana 46202, USA.
10
1] Department of Surgery, University of Colorado, Aurora, Colorado 80045, USA [2] Department of Pharmacology, University of Colorado, Aurora, Colorado 80045, USA [3] University of Colorado Comprehensive Cancer Center, Aurora, Colorado 80045, USA.

Abstract

The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and (1)H-(15)N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.

PMID:
25219851
PMCID:
PMC4351747
DOI:
10.1038/nature13713
[Indexed for MEDLINE]
Free PMC Article

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