Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation

Authors

  • Qi Sun,

    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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    • These authors contributed equally to this work.

  • Dr. Jason P. Burke,

    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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    • These authors contributed equally to this work.

  • Prof. Jason Phan,

    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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  • Michael C. Burns,

    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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  • Prof. Edward T. Olejniczak,

    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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  • Prof. Alex G. Waterson,

    1. Department of Pharmacology, Vanderbilt University School of Medicine, 2200 Pierce Ave., 442 RRB, Nashville, TN 37232 (USA)
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  • Prof. Taekyu Lee,

    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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  • Prof. Olivia W. Rossanese,

    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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  • Prof. Stephen W. Fesik

    Corresponding author
    1. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
    • Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Ave., 607 Light Hall, Nashville, TN 37232 (USA)
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  • This work was supported by the US National Institutes of Health: 5DP1OD006933 (NIH Director’s Pioneer Award) to S.W.F., an ARRA stimulus grant (5RC2A148375) to L. J. Marnett, and a NCI SPORE grant in GI cancer (5P50A095103-09) to R.J. Coffey. This work was also funded by the Lustgarten Foundation grant awarded to S.W.F. and the American Cancer Society (Postdoctoral Fellowship, PF1110501CDD) to J.P.B. We thank Matt Mulder (Craig Lindsley lab, Vanderbilt University) for providing HRMS data.

Abstract

original image

Looking for fragments: A fragment-based screen using NMR spectroscopy was applied to discover ligands that bind to the GTPase K-Ras and modulate the activity of the nucleotide exchange factor Sos. Structural data on how these fragment-derived hits bind to the guanosine diphosphate–K-Ras complex (see picture) provides a starting point for the future discovery of drugs that target K-Ras activation and signaling.

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