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 Meroueh, Dan Theodorescu

Research output: Contribution to journalArticle

64 Citations (Scopus)

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

Fingerprint

GTP Phosphohydrolases
ras Proteins
Neoplasms
Growth
Calorimetry
Surface Plasmon Resonance
RNA Interference
Heterografts
Spectrum Analysis
Magnetic Resonance Spectroscopy
Fibroblasts
Neoplasm Metastasis
Cell Line
Therapeutics
Research
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • General

Cite this

Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., ... 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

Discovery and characterization of small molecules that target the GTPase Ral. / Yan, Chao; Liu, Degang; Li, Liwei; Wempe, Michael F.; Guin, Sunny; Khanna, May; Meier, Jeremy; Hoffman, Brenton; Owens, Charles; Wysoczynski, Christina L.; Nitz, Matthew D.; Knabe, William E.; Ahmed, Mansoor; Brautigan, David L.; Paschal, Bryce M.; Schwartz, Martin A.; Jones, David N M; Ross, David; Meroueh, Samy; Theodorescu, Dan.

In: Nature, Vol. 515, No. 7527, 20.11.2014, p. 443-447.

Research output: Contribution to journalArticle

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, S & Theodorescu, D 2014, 'Discovery and characterization of small molecules that target the GTPase Ral', Nature, vol. 515, no. 7527, pp. 443-447. https://doi.org/10.1038/nature13713
Yan C, Liu D, Li L, Wempe MF, Guin S, Khanna M et al. Discovery and characterization of small molecules that target the GTPase Ral. Nature. 2014 Nov 20;515(7527):443-447. https://doi.org/10.1038/nature13713
Yan, Chao ; Liu, Degang ; Li, Liwei ; Wempe, Michael F. ; Guin, Sunny ; Khanna, May ; Meier, Jeremy ; Hoffman, Brenton ; Owens, Charles ; Wysoczynski, Christina L. ; Nitz, Matthew D. ; Knabe, William E. ; Ahmed, Mansoor ; Brautigan, David L. ; Paschal, Bryce M. ; Schwartz, Martin A. ; Jones, David N M ; Ross, David ; Meroueh, Samy ; Theodorescu, Dan. / Discovery and characterization of small molecules that target the GTPase Ral. In: Nature. 2014 ; Vol. 515, No. 7527. pp. 443-447.
@article{e09b8bfdea9146b5a742d94702fde256,
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 Samy Meroueh and Dan Theodorescu",
year = "2014",
month = "11",
day = "20",
doi = "10.1038/nature13713",
language = "English",
volume = "515",
pages = "443--447",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7527",

}

TY - JOUR

T1 - Discovery and characterization of small molecules that target the GTPase Ral

AU - Yan, Chao

AU - Liu, Degang

AU - Li, Liwei

AU - Wempe, Michael F.

AU - Guin, Sunny

AU - Khanna, May

AU - Meier, Jeremy

AU - Hoffman, Brenton

AU - Owens, Charles

AU - Wysoczynski, Christina L.

AU - Nitz, Matthew D.

AU - Knabe, William E.

AU - Ahmed, Mansoor

AU - Brautigan, David L.

AU - Paschal, Bryce M.

AU - Schwartz, Martin A.

AU - Jones, David N M

AU - Ross, David

AU - Meroueh, Samy

AU - Theodorescu, Dan

PY - 2014/11/20

Y1 - 2014/11/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84911479371&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911479371&partnerID=8YFLogxK

U2 - 10.1038/nature13713

DO - 10.1038/nature13713

M3 - Article

C2 - 25219851

AN - SCOPUS:84911479371

VL - 515

SP - 443

EP - 447

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7527

ER -