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Title page for ETD etd-12052014-101242


Type of Document Dissertation
Author Burns, Michael Charles
Author's Email Address michael.c.burns@vanderbilt.edu
URN etd-12052014-101242
Title Small Molecule Modulation of the Ras-SOS Interaction in Cancer
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Stephen W. Fesik Committee Chair
Jennifer Pietenpol Committee Member
Lawrence Marnett Committee Member
Scott Hiebert Committee Member
Keywords
  • Ras
  • SOS
  • nucleotide exchange
Date of Defense 2014-07-08
Availability unrestricted
Abstract
Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. This dissertation describes the discovery of small molecules that can both inhibit and activate SOS-catalyzed Ras activation. Chapter II describes small molecules that bind directly to Ras that inhibit SOS-catalyzed nucleotide exchange on Ras in a competitive manner. Chapter III describes an investigation examining small molecules that activate SOS-catalyzed nucleotide exchange in vitro and modulate Ras signaling pathways in cells. This study has revealed valuable tool compounds that alter the Ras-SOS interaction by binding to a previously uncharacterized small molecule binding site on the Ras:SOS:Ras complex. X-ray crystallography of Ras:SOS:Ras in complex with these molecules revealed that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. Treating cells with these compounds resulted in an increase in Ras-GTP levels and disruption of MAPK and PI3K signaling at low micromolar concentrations. Chapter IV describes efforts to improve these molecules by conducting a high-throughput screen of the VICB library, and Chapter V describes ongoing investigations into the possible mechanisms of action underlying the perturbed signaling observed downstream of Ras following compound treatment. Chapter VI includes a discussion of the work conducted in this dissertation and describes future directions based on this work. These small molecules represent new tools to study the acute activation of Ras and form the basis for a new approach to target Ras in cancer.
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