2020 Theses Doctoral

Investigations into the Development of Epothilones as Antibody-Drug Conjugate Payloads

Imlay, Hunter David

Cytotoxic natural products represent a class of cancer drug candidates that have remained largely untapped as payloads in the antibody-drug conjugate (ADC) therapeutic modality. The epothilones, a class of exquisitely cytotoxic natural products and their synthetic analogs, are a prime example, and our work has focused on the development of epothilones as ADC payloads. Strategies toward this goal have included total synthetic efforts toward four structurally distinct epothilone analogs equipped with linker functionality and structural modifications designed to improve metabolic and chemical stability. In addition, we have pursued the synthesis of octreotide- epothilone conjugates, structures designed to target epothilones into cells that overexpress somatostatin receptors 2 and 5. Biological evaluation via in vitro cellular assays revealed one of our epothilone analogs as a promising epothilone-inspired ADC payload. Synthetic efforts toward these goals will be discussed.