Discovery and characterization of small molecules that target the GTPase Ral

Chao 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

Research output: Contribution to journalArticle

75 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)443-447
Number of pages5
JournalNature
Volume515
Issue number7527
DOIs
StatePublished - Nov 20 2014
Externally publishedYes

ASJC Scopus subject areas

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    Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., Meier, J., Hoffman, B., Owens, C., Wysoczynski, C. L., Nitz, M. D., Knabe, W. E., Ahmed, M., Brautigan, D. L., Paschal, B. M., Schwartz, M. A., Jones, D. N. M., Ross, D., Meroueh, S. O., & Theodorescu, D. (2014). Discovery and characterization of small molecules that target the GTPase Ral. Nature, 515(7527), 443-447. https://doi.org/10.1038/nature13713