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

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.
AuthorsChao Yan, Degang Liu, Liwei Li, Michael F Wempe, Sunny Guin, May Khanna, Jeremy Meier, Brenton Hoffman, Charles Owens, Christina L Wysoczynski, Matthew D Nitz, William E Knabe, Mansoor Ahmed, David L Brautigan, Bryce M Paschal, Martin A Schwartz, David N M Jones, David Ross, Samy O Meroueh, Dan Theodorescu
JournalNature (Nature) Vol. 515 Issue 7527 Pg. 443-7 (Nov 20 2014) ISSN: 1476-4687 [Electronic] England
PMID25219851 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • GTPase-Activating Proteins
  • RALBP1 protein, human
  • Small Molecule Libraries
  • ral GTP-Binding Proteins
  • ras Proteins
Topics
  • ATP-Binding Cassette Transporters (metabolism)
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Computer Simulation
  • Drug Screening Assays, Antitumor
  • Female
  • GTPase-Activating Proteins (metabolism)
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Targeted Therapy
  • Neoplasms (drug therapy, enzymology, metabolism, pathology)
  • Protein Binding (drug effects)
  • Signal Transduction (drug effects)
  • Small Molecule Libraries (chemistry, pharmacology)
  • Substrate Specificity
  • Xenograft Model Antitumor Assays
  • ral GTP-Binding Proteins (antagonists & inhibitors, chemistry, metabolism)
  • ras Proteins (metabolism)

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