Illudalogs  -Phosphatase
Inhibitors

Phosphatase inhibitors are an up-and-coming hot topic as clinical cancer treatments, however, some phosphatases lack the necessary chemical tools to validate them as therapeutically relevant targets let alone to develop lead compounds into potential drugs. Traditional high throughput screening for Protein Tyrosine Phosphatase (PTP) ligands result in charged compounds with low bioavailability and selectivity due to the PTP’s highly conserved active site and positively charged surface. Illudalic acid, a natural product from the “Jack O’Lantern” mushroom, overcomes these bioavailability and selectivity challenges. In collaboration with the Dudley lab from West Virginia University, this project has designed and synthesized an ongoing library of illudalic acid analogs or “illudalogs” as inhibitors of PTP activity. The goal of this work is to develop illudalogs as selective, potent, and bioavailable inhibitors of PTP activity to study PTP enzymology, PTP signaling, and the role of PTPs in disease. This project strives to understand the enzymology, structure activity relationship (SAR), pharmacophores, mechanism of inhibition, and structural paradigms for how these illudalogs inhibit PTP activity as well as apply them to biological questions. We have so far developed novel compounds with nanomolar potency for the LAR subfamily of PTPs (PTPRD, PTPRS, and LAR) with direct animal model applications for the treatments and understanding of opioid and stimulant addiction (Keefe lab and Peterson lab, University of Utah). This project is highly collaborative and includes ongoing work with the Dudley lab (West Virginia University, synthesis and rational design), Keefe lab (University of Utah, rat model of addiction), Peterson lab (University of Utah, zebrafish model of addiction), Cheatham lab (University of Utah, computational modeling and in silico screening), and the Holland lab (University of Utah, insulin resistance). Students who work on this project with learn drug development from the early stages of lead compound identification and design up to cellular validation and animal model development.