OCT 30, 2014 1:30 PM PDT

Dissecting cancer signaling pathways with chemical scalpels

Speaker
  • Head, Synthetic Biologics Core, Cancer and Inflammation Program, Center for Cancer Research National Cancer Institute
    Biography
      Dr. Tarasova was trained as a bioorganic chemist. She obtained her Ph.D. in chemistry at Lomonosov University, Moscow, Russia in 1981. After post-doctoral training in the lab of Prof. Bent Foltmann at Copenhagen University, Denmark, she established a group working on the chemistry of proteolytic enzymes in the Chemistry Department of Lomonosov University. Dr. Tarasova joined the ABL-Basic Research Program of NCI as Visiting Scientist in 1991 and became a Staff Scientist in NCI Center for Cancer Research in 1999. She was appointed a Head of Synthetic Biologics and Drug Discovery Facility in 2008.

    Abstract

    Advances in genomic research have led to identification of the majority of the drivers of tumor progression. However, our understanding of the molecular mechanisms propelling tumor growth is progressing much slower. Incomplete knowledge of oncoproteins regulatory mechanisms results in unexpected detrimental effects of targeted therapy. Obliteration of the protein expression is the most commonly used approach in characterization of protein function. However, the majority of proteins have multiple functions and many interacting partners. Genetic eradication of proteins does not inform on the function of particular protein-protein interactions and cannot detect essential self-inhibitory mechanisms. Chemical biology tools are much more informative in that sense. However, generation of selective chemical probes is a labor-intense process. In addition, the majority of protein-protein interactions cannot be inhibited by small molecules and thus are considered undruggable. Peptides are well suited for targeting protein-protein interactions, but their use is hampered by conformational flexibility, poor membrane penetration, low stability in circulation and rapid clearance from the body. We and others we have succeeded recently in developing metabolically stable cell permeable peptide analogs with rigid and predictable structures amenable to rational design. The approach developed in our group is based on structural stabilization of protein fragments by membrane anchoring. General applicability of this straightforward method was confirmed by generation of selective and highly potent dominant negative inhibitors of RAS oncogenes, ?-catenin, STAT1, STAT3 and STAT5 N-domains, and other non-druggable targets. Much simplified generation of selective chemical biology tools allows for effective interrogation of protein-protein interactions leading to uncovering of mechanistic details of molecular signaling that could not be obtained with the help of genetic approaches.

    Learning objectives:

    • Learn simple ways of developing chemical biology tools (no sophisticated chemistry is required)
    • Learn how to uncover the roles of a certain protein-protein interaction.

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