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

Fragmentsuche: Liganden, die an die GTPase K-Ras binden und die Aktivität des Nukleotidaustauschfaktors Sos verändern, wurden mit einem fragmentbasierten Screening unter Verwendung von NMR-Spektroskopie gefunden. Strukturdaten zeigen, wie die von den Fragmenten abgeleiteten Treffer an den K-Ras-Guanosindiphosphat-Komplex binden (siehe Bild), und liefern einen Ausgangspunkt für die Entwicklung von Wirkstoffen, die K-Ras-Aktivierung und -Signalisierung beeinflussen.

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