Graduation Year
2025
Document Type
Campus Only Senior Thesis
Degree Name
Bachelor of Arts
Department
Chemistry
Reader 1
Dr. Mira Liu
Reader 2
Dr. Paul Hergenrother
Terms of Use & License Information
Rights Information
© 2024 Anna F Ermoian
Abstract
Non-small cell lung cancers (NSCLCs) account for ~85% of all lung cancer cases, with advanced forms of NSCLCs having a less than 5% 5-year survival rate. One of the common oncogenic drivers of NSCLCs is an activating mutation of the epidermal growth factor receptor (EGFR). Although targeted therapeutics have been developed to treat EGFR NSCLC, resistance to earlier generation inhibitors is common. Osimertinib is the current standard of care for EGFR NSCLC patients. Aumolertinib, a derivative of osimertinib, is currently in clinical trials in the United States. Both drugs inhibit EGFR via a covalent bond formed with the Cys797 residue in EGFR’s ATP binding pocket; however, resistance occurs after ~10 months, with 20% of resistant cases containing a C797S mutation. Due to serine’s lower nucleophilicity relative to cysteine, the inhibitory covalent bond cannot form. Some small molecule drugs used to treat diseases target serine residues, and research has identified serine-targeting electrophiles that can be appended to third generation EGFR inhibitor scaffolds. We modified the warhead of osimertinib and aumolertinib, and successfully synthesized and characterized three novel small molecules: an osimertinib ⍺-ketoamide, an aumolertinib ⍺-ketoamide, and an β-bromo-osimertinib. These novel molecules were tested for efficacy against wild-type and EGFR NSCLC human cell lines, and we observed low rates of EGFR inhibition. While the molecules still require testing against the C797S mutation, the lack of binding to the other cell lines supports our hypothesis that a serine in the binding pocket will be required for our serine-targeting molecules to bind to EGFR. This is the first time this approach has been used to combat the C797S mutation in NSCLC. If the molecules are selective for serine, this would be the third instance of a small molecule targeting non-catalytic serine, providing insights into expanding the scope of small molecule targets.
Recommended Citation
Ermoian, Anna, "Synthesis and Biological Testing of Novel Epidermal Growth Factor Receptor Inhibitors to Combat the C797S Mutation in Non-Small Cell Lung Cancer" (2025). Scripps Senior Theses. 2529.
https://scholarship.claremont.edu/scripps_theses/2529
This thesis is restricted to the Claremont Colleges current faculty, students, and staff.
