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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Yan, C; Liu, D; Li, L; Wempe, MF; Guin, S; Khanna, M; Meier, J; Hoffman, B; Owens, C; Wysoczynski, CL; Nitz, MD; Knabe, WE; Ahmed, M; Brautigan, DL; Paschal, BM; Schwartz, MA; Jones, DNM; Ross, D; Meroueh, SO; Theodorescu, D

Published Date

  • November 2014

Published In

Volume / Issue

  • 515 / 7527

Start / End Page

  • 443 - 447

PubMed ID

  • 25219851

Pubmed Central ID

  • PMC4351747

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature13713


  • eng