Rho A and Rho C, members of the Rho GTPase family, have been found to have important roles in the metastases of multiple cancers, including melanoma, prostate, and breast cancer. While Rho GTPases are known to have effects on cell morphology, recent evidence has also demonstrated their ability to affect gene transcription. Many of the current inhibitors of the Rho pathway focus on targeting downstream effectors. However, there are few drugs that target gene transcriptional modulation.
Using a cell-based dual Firefly and TK-Renilla luciferase assay, our collaborators in the Neubig laboratory identified a small molecule (1423) that inhibited RhoA/C-stimulated gene expression. Compound 1423 was shown to significantly inhibit gene expression, as well as inhibit the proliferation of a highly metastatic melanoma line and the invasion of PC-3 prostate cancer cells. However, the compound was found to have modest selectivity and significant cytotoxicity. To improve these properties, we examined structure-activity relationships through the synthesis and evaluation of over 100 analogs, focusing on bioisosteric replacement of amide bonds and conformational restriction. We were successful at identifying compounds with improved selectivity for inhibition of RhoA/C-mediated gene transcription and reduced cytotoxicity in comparison to 1423. Finally, we prepared a variety of affinity reagents, which may ultimately provide a novel target for anti-metastatic therapies for cancer. In total, this work advanced 1423 analogs as new inhibitors of the Rho transcriptional signaling pathway.PHDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96163/1/jlbe_1.pd
