Archived

This content is available here for research, reference, and/or recordkeeping.

Author ORCID Identifier

0000-0001-6608-6765

Date Available

8-12-2028

Year of Publication

2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Arts and Sciences

Department/School/Program

Chemistry

Faculty

Samuel G. Awuah

Faculty

Kenneth Graham

Abstract

Master regulatory programs including transcription factors (e.g., MYC), organelles (e.g., mitochondria), and hub proteins, coordinate genetic activity, metabolic state, and stress adaptation across cellular systems. Targeting these programs remains a central challenge in chemical biology, owing to their structural complexity, network redundancy, and context-dependent regulation. Understanding how chemical tools can modulate these interwoven biological networks is essential for overcoming limitations of current therapeutic strategies. This dissertation investigates chemical modulation of two interconnected master regulators: the transcription factor MYC (specifically, cellular myelocytomatosis throughout this dissertation, unless otherwise stated) and the mitochondrion. The MYC family of proteins, including MYC (cellular myelocytomatosis), MYCN (neuroblastoma-derived myelocytomatosis) and MYCL (Lung carcinoma-derived myelocytomatosis) orchestrates broad transcriptional programs in biology, whereas mitochondria govern cellular bioenergetics and redox homeostasis; both frequently dysregulated in cancer and inflammatory diseases.

MYC is a key driver of numerous human cancers yet has long been considered “undruggable” due to its intrinsically disordered structure and lack of conventional ligand-binding pockets. Several existing MYC inhibitors fail due to weak ligand-target MYC interaction, lack of selectivity, uncharacterized off-target effects, and poor in vivo efficacy. To overcome the liabilities, I developed multiple chemical biology strategies for functional MYC engagement. First, through the discovery of MY05, I achieved direct intracellular inhibition of MYC. MY05 selectively disrupts MYC-MAX heterodimerization and attenuates MYC-dependent transcriptional programs in cancer models and demonstrates that intrinsically disordered transcription factors can be meaningfully targeted with small molecules. MY05 further serves as a foundation for the design of next-generation covalent modifiers and degraders of MYC.

In parallel, we employed Metal-mediated Ligand Affinity Chemistry (MLAC) to develop 2-P, a proximity-guided covalent probe. By conjugating the known MYC–MAX disruptor 10058-F4 to an Au(II)-based warhead, we intend to facilitate site-selective cysteine modification within MYC’s intrinsically disordered region to stabilize the small-molecule engagement and enhance potency without relying on traditional binding pockets.

Beyond direct inhibition, I explored indirect regulation of MYC through upstream biochemical control. Chemical modulation of HMOX2 by the small molecule AuMac1 revealed a novel axis that depletes MYC while simultaneously reprogramming mitochondrial function and redox balance. These studies uncover a mechanistic interface between mitochondrial metabolism and oncogenic transcription, demonstrating that bioenergetic state influences MYC-dependent gene expression. Chemical perturbation of mitochondria was further shown to reprogram metabolic states and selectively impair disease-associated phenotypes, positioning mitochondria as key regulatory hubs in proliferative and inflammatory signaling.

Extending this mitochondrial focus to inflammatory contexts, I developed AuPhos, a gold-based agent that modulates mitochondrial respiration as a brain-penetrant agent for tissue repair. AuPhos induces mitochondrial biogenesis, enhances oxidative capacity, suppresses inflammatory signaling, and drives coordinated transcriptional remodeling. In a model of traumatic brain injury, AuPhos-supported mitochondrial enhancement promoted metabolic resilience and tissue repair programs.

Collectively, this work establishes a chemical biology framework for reprogramming transcriptional and bioenergetic master regulators. By combining direct MYC engagement, redox-mediated MYC control, and mitochondria-driven transcriptional remodeling, these studies provide new tools and mechanistic insights with potential applications in oncology and neuroinflammation.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.415

Archival?

Archival

Funding Information

This work was supported by National Science Foundation Chemistry of Life Processes (NSF-CLP) grant for S.G.A. (Award CHE-2203559), National Cancer Institute (NCI) R01CA258421, Kentucky Spinal Cord Injury Research Trust, #22-2A (S.G.A), Cancer Research Informatics Shared Resource of the University of Kentucky Markey Cancer Center (P30CA177558), Center for Pharmaceutical Research and Innovation (National Institutes of Health P20GM130456). The UK NMR Center is supported by National Science Foundation (CHE-997738).  UK Flow Cytometry, Pathology and Immune Function core supported by the Office of the Vice President of Research and National Cancer Institute (NCI) Center Core Support Grant (P30 CA177558). 

Download

Available for download on Saturday, August 12, 2028

Contact Author

Share

COinS