Date of Award

2022

Embargo Period

5-19-2022

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

First Advisor

Russell (Chip) Norris

Second Advisor

Thomas Dix

Third Advisor

Kris Helke

Fourth Advisor

Patrick Woster

Fifth Advisor

Yuri Peterson

Abstract

Pharmacokinetics (PK) is the study of how the body interacts with xenobiotics, encompassing the kinetics of absorption, distribution, metabolism, excretion, and toxicity (ADMET). The ADMET properties of chemical entities play a pivotal role in drug discovery and development. Drugs of high quality should not only have sufficient affinity, selectivity, and potency, but must also possess suitable ADMET properties at a therapeutic dose. The drug failure rate is high, with less than 10% of drug candidates making it to the market after reaching Phase I clinical trials. PK issues are the most common reason for drug failure, often due to unexpected toxicity. As such, special emphasis should be placed on PK optimization in early-stage drug discovery. This dissertation reviews and implements tools used to optimize peptide and small molecule drug candidates. In aim 1, we used non-natural amino acids and a specialized ethylene-vinyl acetate (EVA) delivery system to optimize the PK of a kappa opioid receptor agonist (KOA) peptide, CR665. In doing so, we discovered TP-2021, a highly potent KOA (EC50 = 52 pM) with profound selectivity and anti-pruritic activity. Prototype EVA polymer implants were able to sustain supratherapeutic plasma concentrations of TP-2021 in a mouse model of chronic pruritus for up to four months. IND-enabling studies are ongoing. In aim 2, we elucidated the cellular and mechanisms of MEK1-inhibitor induced cardiotoxicity. Trametinib-treated animals experienced a decline in cardiac function. Transcriptomic and iPathway analysis identified IL-6 as an activator of PI3K/AKT and JAK/STAT signaling pathways, with downstream changes in genes associated with hypertrophy, cell survival, mitochondrial biogenesis, mitophagy, and oxidative stress. Key histological changes included a loss of cardiomyocyte apelin receptor expression, connexin-43 mislocalization, extracellular matrix remodeling, and, in 23% of cases, myocardial calcification and vacuolization. Additionally, FDA-approved MEK1 inhibitors block hERG, putting patients at risk for life threatening arrhythmias. Harnessed with this information, we employed a novel machine learning-based workflow to design MEK1 inhibitors with improved pharmacokinetics. Two nanomolar range candidates devoid of hERG and cytochrome P450 (CYP) interactions were identified and are undergoing further in vivo testing. Insights from this work may be replicated to design safer drug candidates.

Rights

All rights reserved. Copyright is held by the author.

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