The Synthesis and Exploration of Potential New Antagonists of the Wnt Signaling Pathway: New Leads to Treat Colon Cancer? Or, Not Quite?

Colorectal cancer continues to be a major health concern with over 150,000 new cases diagnosed each year in the United States alone. Nonetheless, the mutations that drive colorectal cancer are among the best characterized of any human tumor, proffering immense potential for therapeutic targets. In particular, levels of B-catenin are invariably increased in colorectal tumors, a state accompanied by dysregulation of the Tcf/B-catenin complex. As such, disruption of this interaction makes for an attractive drug target. With the goal of targeting the B-catenin/Tcf complex, several series of pyrimidotriazinediones, pyrimidopyridazinediones, pyrrolopyrimidinediones, and pyrazolopyrimidinediones were synthesized. Testing of analogues was carried out in an in vitro ELISA binding assay with purified B-catenin and Tcf4-GST proteins and by a colloborating lab in a functional in vitro assay that used rat epithelial (IEC18) cells transfected with the TOPFLASH luciferase reporter gene to measure inhibition of the B-catenin/Tcf complex. Due to conflicting results between the two assays, synthesized analogues were also tested versus firefly luciferase in vitro to assess potential interference from inhibition of the reporter itself in the cellular assay. Overall, many of the synthesized compounds were found to be potent inhibitors of firefly luciferase with a clear structure-activity relationship for luciferase inhibition, but there was also evidence that some analogues displaying activity in the cellular assay were also affecting the Wnt signaling pathway. One of these analogues was analyzed for its pharmacokinetic properties, which are sufficiently promising in a mouse study to encourage future studies against a mouse colon xenograft model to assess potential in vivo efficacy.Ph.D.Medicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64688/1/koritnik_3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/64688/2/koritnik_2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/64688/3/koritnik_1.pd

Novel Peptide Ligands of RGS4 from a Focused One-Bead, One-Compound Library

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65605/1/j.1747-0285.2008.00687.x.pd