Description:

Paul Trippier, PhD
Assistant Professor of Medicinal Chemistry
School of Pharmacy, Texas Tech University Health Sciences Center 

Oncology and Neurodegeneartive Disease Drug Discovery, With or Without Known Targets

The traditional undertaking of drug discovery is based on the rational design of compounds to optimize potency at a known receptor or protein target along with engendering desirable ADME properties. However, in many rare and neurological disorders little is known about the pathophysiology of the disease, making rational drug discovery impossible. In these ill-understood diseases, compound optimization and target identification proceed hand in hand. This seminar will describe two projects in my lab that approach drug discovery from these two separate directions.
The enzyme aldo-keto reductase 1C3 (AKR1C3) performs a key role in the progression of castration-resistant prostate cancer (CRPC), an advanced, drug-resistant, highly aggressive form of prostate cancer. In addition to making CRPC tumors self-sustaining by producing a source of intra-tumoral androgens that drive proliferation, the enzyme has been shown to mediate resistance to the two clinically available chemotherapeutics. Two highly homologous isoforms are known that possess anti-proliferative activity, thus selectivity is crucial. The design of highly potent and isoform selective inhibitors of AKR1C3 has been challenging to date. Herein, we describe the synthesis of the most selective AKR1C3 inhibitors known (>2800-fold selectivity) and characterize their effects in in vivo and in vitro models of CRPC.
Juvenile Neuronal Ceroid Lipofucinosis (JNCL) is a rare neurodegenerative disease that predominately affects children. No cure or effective treatment exists. Together with our collaborators we have identified a scaffold that confers protective activity in patient-derived lymphoblasts. Optimization has led to the identification of drug leads and chemical probes that are active at 100 nM concentration in functional human neurons derived from induced pluripotent stem cells (iPSCs), the most translatable model of human neurons currently available. We describe a novel multi-modal mechanism of neuroprotective action that is applicable across neurodegenerative diseases and have characterized a novel phenotypic model of JNCL in human neurons derived from patient-specific iPSCs. We demonstrate rescue of multiple phenotypes of JNCL upon treatment with our developed compounds.