@article{b1bea59a03b544abb60562ee0bdc7791,
title = "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.",
author = "Chao Yan and Degang Liu and Liwei Li and Wempe, {Michael F.} and Sunny Guin and May Khanna and Jeremy Meier and Brenton Hoffman and Charles Owens and Wysoczynski, {Christina L.} and Nitz, {Matthew D.} and Knabe, {William E.} and Mansoor Ahmed and Brautigan, {David L.} and Paschal, {Bryce M.} and Schwartz, {Martin A.} and Jones, {David N.M.} and David Ross and Meroueh, {Samy O.} and Dan Theodorescu",
note = "Funding Information: Acknowledgements This work was supported in part by NIH grants CA091846, CA075115, CA104106 and GM47214 by the IUPUI Research Scholar Grant Foundation and by an American Cancer Society Research Scholar grant. The researchers used the services of the Medicinal Chemistry Core (MCC) facility (M.F.W.) housed within the Department of Pharmaceutical Sciences, University of Colorado. In part, the MCC is funded by Colorado Clinical and Translational Sciences Institute grant UL1TR001082 from the National Center for Research Resources, NIH. We acknowledge D. S. Backos for assistance with computational modelling, A. Spencer for biochemical assays, B. Helfrich for assistance with lung cancer cell line culturing, and H. Mo and J. Harwood for assistance in the training and collection of NMR data in the early stages of the project. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",
year = "2014",
month = nov,
day = "20",
doi = "10.1038/nature13713",
language = "English (US)",
volume = "515",
pages = "443--447",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7527",
}