Date of Award
Fall 11-21-2025
Document Type
Dissertation
Degree Name
Ph.D. in Chemistry and Biochemistry
Organizational Unit
College of Natural Science and Mathematics, Chemistry and Biochemistry
First Advisor
Sunil Kumar
Second Advisor
Daniel Paredes
Third Advisor
Scott Horowitz
Fourth Advisor
Michelle Knowles
Fifth Advisor
Martin Margittai
Copyright Statement / License for Reuse
All Rights Reserved.
Keywords
Cancer, KIX, Mixed-lineage leukemia (MLL), Neurodegenerative diseases
Abstract
Protein-protein interactions (PPIs) are critical for the physiological growth, development, and maintenance of all cells throughout the human body. However, genetic mutations, aging, and environmental exposures can lead to the induction of aberrant PPIs (aPPIs), which have been implicated in various ailments, including cancer and neurodegenerative diseases. Researchers have identified and tested various ligands, with a range of molecular weights, that can modulate the onset and propagation of these non-infectious diseases. In 2001, Hamilton et al. introduced a new class of small-molecule drugs, called oligopyridylamides (OPs), which are α-helical protein mimetics that interact with the i, i + 3/4, and i + 7 residues on one face of the α-helix on the protein of interest. These molecules have been previously reported to attenuate the phenotypes associated with type II diabetes, p53-mediated tumorigenesis, Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Lewy Body Disease (LBD). Interestingly, OPs are considered to be versatile as they can be easily modified to enhance the specificity and binding affinity toward the target protein without sacrificing their pharmaceutical properties, such as cell and blood-brain barrier (BBB) permeability, and enzymatic stability.
Given that OPs can directly bind and inhibit aggregation-prone proteins like α-Synuclein (αS) and Amyloid-β (Aβ) in PD and AD, respectively, we sought to investigate the versatility of OPs against the pathological phenotypes associated with mixed-lineage leukemia (MLL)-rearrangement (MLL-r) leukemia. The onset of MLL-r leukemia is typically initiated via a chromosomal translocation involving the MLL protein and one of its various fusion protein partners (AF4, AF9, ENL, and ELL). Using an acute lymphoblastic leukemia (AML) cell line (MV4-11), which bears the t(4;11)(q21;q23) mutation, we examined the effect of the identified potent OP, NS166, on cytotoxicity, apoptosis activation, and cell cycle arrest. We subsequently tested NS166 on a control breast cancer cell line (MCF-7) and compared the results to the MV4-11 cell line. Our results suggested that NS166 induces the apoptotic pathway via arresting the cell cycle at the G0/G1 phase in MV4-11 cells. We foresee the use of OPs as the standard approach to specifically target and inhibit the onset and progression of cancer and neurodegenerative diseases.
Copyright Date
11-2025
Publication Statement
Copyright is held by the author. User is responsible for all copyright compliance.
Rights Holder
Tyler David Ball
Provenance
Received from ProQuest
File Format
application/pdf
Language
English (eng)
Extent
150 pgs
File Size
4.1 MB
Recommended Citation
Ball, Tyler David, "Targeting Aberrant Protein-Protein Interactions in Cancer and Neurodegenerative Diseases" (2025). Electronic Theses and Dissertations. 2664.
https://digitalcommons.du.edu/etd/2664