Author ORCID Identifier
Date Available
8-12-2023
Year of Publication
2021
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Arts and Sciences
Department/School/Program
Chemistry
First Advisor
Dr. Samuel Gorman Awuah
Abstract
Protein-protein interactions (PPIs) are vital to many biological processes, including gene expression, and immune reactions to pathogens. There are approximately 650,000 PPIs in humans with pertinent physiological functions. Aberrant expression of PPIs lead to improper function and contribute to a plethora of disease conditions including cancer. Thus, PPIs represent an enormous target space for drug discovery and chemical probes. Direct targeting of clinically relevant PPIs with small molecules remains an unmet medical need. Development of small-molecule inhibitors of PPIs is a challenging enterprise and in most cases considered undruggable due to large protein surfaces, lack of deep binding pockets and enzymatic activities. Despite these limitations, significant progress has been made in the area of compound development that selectively target oncogenic PPIs and those underlying inflammation.
This work focuses on synthetic strategies based on rational design towards the development of small-molecule inhibitors of PPIs. The approaches developed herein are applied to distinct protein targets, including the proto-oncogene product c-MYC, which dimerizes with MAX; the immunotherapeutic target programmed death receptor (PD-1) and programmed death ligand receptor (PD-L1), and the epigenetic target AT-rich interacting domain 4B (ARID4B). Further, the fundamentals of the small-molecule drug discovery process is covered. Specifically, using computational methods and synthetic chemistry gold-based small-molecule covalent inhibitors of the intrinsically disordered protein, MYC, were developed. First-in-class small-molecule inhibitors, with diverse structure-activity relationship (SAR), for the inhibition of ARID4B were also discovered. Dual-action small molecule inhibitors that perturb both Poly(ADP-ribose) polymerase (PARP) and PD-1/PD-L1 pathways were developed. Finally, novel frameworks for targeting PD1/PD-L1 were also developed.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2021.328
Funding Information
Financial support for this study was provided by the University of Kentucky (UK) between 2017 -2021. This study made use of the University of Kentucky Nuclear Magnetic Resonance (UK NMR) facility, with funds from the Magnetic Resonance Imaging (MRI) Program (grants -0319176 and -1625732) (from 2017 - 2021) as well as the University of Kentucky Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and the National Cancer Institute Center Core Support Grant (177558) (from 2017 - 2021) to the University of Kentucky Markey Cancer Center. This study also made use of funds provided by the Center for Pharmaceutical Research and Innovation / National Institutes of Health Exploratory Grant (130456) (from 2017 - 2021).
Recommended Citation
Ofori, Samuel, "Rational Design of Small Molecule Disruptors of Protein-Protein Interactions: PD-1/PD-L1; c-MYC, ARID4B" (2021). Theses and Dissertations--Chemistry. 146.
https://uknowledge.uky.edu/chemistry_etds/146
