Abstract

Targeted inhibition of oncogenes has remained a key strategy in the development of more potent, effective, and less toxic therapeutic anticancer agents. Among the most clinically significant signaling pathways are those mediated by the Human Epidermal Growth Factor Receptor 2 (HER2) and Aurora Kinase A (AurKA). HER2 is a member of the ErbB receptor family that supports cell growth and proliferation through downstream signaling of the PI3K and MAPK pathways and is closely linked to more aggressive tumors and therapeutic resistance. AurKA is a protein kinase essential for mitotic spindle assembly, centrosome maturation, and other key processes in cell cycle progression. Since the dysregulation and overexpression of these proteins serve as key drivers of cancer growth, selective inhibitors have the potential to improve current limitations in treatment and overcome resistance. In this study, we analyzed several broad libraries of chemically diverse inhibitors for each protein. For HER2, we identified several inhibitors with similar potency, structure, and lower toxicity than the parent compound. Cellular assays were used to determine potency, selectivity, and toxicity. HER2 inhibition was further verified with RT-PCR. Two compounds, 10 and 13 showed significant inhibition with IC50 values of 42.51 and 77.2μM. These will be advanced for in-vivo assays. For AurKA, we identified and determined the binding mode of two potential inhibitory compounds, 20 and 30. Molecular docking software provided additional insight into predicted binding modes. Michaelis-Menten kinetics were used to determine mechanisms of inhibition in AurKA. Our results found that the AurKA inhibitors bound in an ATP-competitive manner with IC50 values of 101.759 μM and 51.02 μM, respectively. This study identified two HER2 inhibitors with significantly higher potency than the parent compound alongside two AurKA inhibitors that showed ATP competitive binding, highlighting selective targeting for both oncogenic pathways.

Date of publication

Spring 2026

Document Type

Thesis

Language

english

Persistent identifier

http://hdl.handle.net/10950/5059

Committee members

Dr. Jiyong Lee, Dr. May Abdelaziz, Dr. Dustin Patterson

Degree

Masters in Chemistry

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Chemistry Commons

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