John Blobe

Date of Award

2024

Document Type

Thesis

Degree Name

Bachelor of Science

Department

Biochemistry & Molecular Biol.

First Advisor

Dr. Christopher Shugrue

Abstract

As cancer cases continue to rise, the need for advancing the treatment options for cancer is ever increasing. Current cancer therapeutics, while effective at treating localized cancers and a fraction of advanced cancers, generally lack the specificity needed to target more advanced cancers. Recent advancements in cancer treatments have leveraged antibodies to target certain cancers. A class of drugs that utilize antibodies to deliver anti-cancer therapy preferentially to cancer cells, termed antibody-drug conjugates (ADCs), have been quite effective in treating certain advanced forms of certain cancers. These ADCs could be more effective if they could allow for the facile release of the anti-cancer therapy by engineering in a cleavable linker. Here we explore the use of heterocycles as peptide-based cleavable linkers, which could be used in the development of novel ADCs. Two primary heterocycles were explored for their utility as peptide-based cleavable linkers, oxazoles and benzothiazoles. Oxazoles can function as cleavable linkers through the 4+2 cycloadditions with alkynes. Benzothiazoles can function as cleavable Estele linkers through nucleophilic aromatic substitution (SNAr). We demonstrate that benzothiazoles have promise as peptide-based cleavable linkers due to their ability to be added to peptides through the SNAr with cysteine’s nucleophilic thiol. Peptide-bound benzothiazoles are quantitatively cleaved from peptides within 3 hours at room temperature. Further exploration of benzothiazoles as cleavable linkers could assist in the development of new therapeutics for cancer as well as other diseases.

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