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

doi:10.1038/nature13713

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

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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 language	English (US)
Pages (from-to)	443-447
Number of pages	5
Journal	Nature
Volume	515
Issue number	7527
DOIs	https://doi.org/10.1038/nature13713
State	Published - Nov 20 2014

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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

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 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

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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",

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doi = "10.1038/nature13713",

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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 O.

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.

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Discovery and characterization of small molecules that target the GTPase Ral

Abstract

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