| The Rho family of small molecule GTPases plays a critical role in the development and manipulation of the cytoskeleton. These proteins act to affect changes in cell morphology, polarization and locomotion. Additionally, many members of the Rho family, including the well characterized proteins RhoA, Cdc42 and Rac1, have been implicated in numerous cancers, and particularly in the metastasis of relevant tumors.;The enclosed work describes multiple approaches to the inhibition of Rho family GTPase signaling, focusing in particular upon family member RhoA and its effectors. Families of inhibitors are reported which specifically target the Rho-Geranylgeranyltransferase I interaction, the RhoA effector Rho kinase, and the interaction between RhoA and its activator, Dbs. Of these targets, geranylgeranyltransferase I inhibition has been well reported in the literature, as has Rho kinase inhibition. Very little work has previously been done to block the interaction between RhoA and Dbs, and RhoA's subsequent activation.;Special attention is paid herein not only to the synthetic preparation of molecules, but the inclusion of computational design and analysis techniques and the use of biological assay to inform decisions made at each stage of inhibitor development. Additionally, projects are described which start at varying levels of maturity, with one project meant to further optimize a set of well developed inhibitors and another meant to design inhibitors de novo for a protein-protein interaction never before interrupted. Similarly, a wide variety of molecules are reported, from small coumarins and phthalamides to multimeric peptides and advanced peptiomimetics. Low muM affinity compounds are presented for each system investigated. |
