A major cause of cancer related deaths is due to the metastasis of malignant cells from the primary tumor to other tissues. Aberrant activity of the regulatory Rho family GTPases has been identified as one of the underlying biochemical processes for initiation of this cell migration to occur. In our laboratory we discovered the small molecule inhibitor EHop-016, and showed that it was able to inhibit the interaction of the proto-oncogene Vav2 with the Rho GTPase Rac1. When EHop-016 binds to Rac, it prevents its activation by the GEF Vav2. This inhibits Rac-stimulated processes such as lamellipodia formation, cell migration, and metastasis. We have shown that EHop-016 reduces tumor growth and metastasis in in vivo experiments in mice. In the first aim of this proposal, a structural optimization of EHop-016 will be carried to obtain a compound with increased activity, reduced toxicity and optimized pharmacochemical parameters. This is expected lead to a compound that is suitable for pre-clinical investigation that could eventually become a novel pharmacotherapeutic agent against cancer. In the second aim of the proposal, new agents that inhibit Vav-Rac interaction will be designed that bind to Vav instead of to Rac. This will provide small molecule inhibitors of Vav-Rac interaction with an alternative mode of action. We have access to three different tumor cell lines that each predominantly express one of the isoforms of the GEF, Vav1, Vav2 or Vav3. Similar as the Rac-binding inhibitor EHop-016, Vav-binding inhibitors are hypothesized to inhibit lamellipodia formation, cell migration and metastasis. With the discovery of new Vav binders, a new molecular probe for the investigation of GTPase activities will become available. Moreover, further optimization of these novel inhibitors could potentially lead to therapeutic agents that will have a complementary or additive effect with EHop-016 or its improved derivatives.
The proposed research will lead to the development of new molecules that can be used to study the mechanisms by which tumor cells grow and metastasize. A better understanding of these processes and further optimization of the activities of the new compounds could lead to the development of novel drugs for the treatment of cancer.
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