Rational Design of Rho Protein Inhibitors

Rho GTPases are molecular switches that fluctuate between on and off states. When active, these proteins function to remodel the actin cytoskeleton by interacting with a number of downstream effector molecules. Recent studies have linked the activation of Rho GTPases with the acquisition of a metastatic phenotype in many types of cancers especially breast cancer. This proposal incorporates a rational approach to target these signaling proteins using small molecule inhibitors that would interfere with their ability to become activated by Rho family guanine nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.