Graduation Year
2024
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Chemistry
Major Professor
Jianfeng Cai, Ph.D.
Committee Member
David Merkler, Ph.D.
Committee Member
Feng Cheng, Ph.D.
Committee Member
Wenqi Liu, Ph.D.
Keywords
PROTAC, Sulfono-γ-AApeptide, SPPS, Michael receptor, HPLC purification, Cleavage cocktail
Abstract
This report mainly discusses the development of RET Proteolysis targeting chimera PROTAC molecules based on Selpercatinib (LOXO-292) and Sulfono-γ-AApeptide PROTAC. A PROTAC molecule is a bifunctional molecule composed of two active domains and a linker. It works by inducing selective protein intracellular degradation. This technology was first discussed by Kathleen Sakamoto, Ray Deshaies and Craig Crews in 2001. Using various E3 Ligase, such as CRBN, pVHL, beta-TrCP1, Mdm2, DCAF15, DCAF16, RNF114, and c-IAP1, the PROTAC technology has been applied to several novel drug development,. Yale University licensed the PROTAC technology to Arvinas in 2013–14. For my research, Chapter one summarizes our development of RET PROTAC in detail. Using Selpercatinib as warhead binding to RET protein, different methylene, PEG and heterocycle linkers, various E3 ligases are also tried to develop RET proteac molecues. Chapter two discusses our novel design of covalent inhibitors that targets RET G810C mutation using different Michael receptors. Chapter three concludes our design of unnatural γ-AApeptide to overcome antibiotic resistance due to the abuse of current antibiotics. Chapter four starts with the basic knowledge of solid phase synthesis. After the brief review, our research on the SPPS of BCL-9 sulfono-γ-AApeptide PROTAC linked with VHL and PG E3 ligase is discussed. Details of sulfono-γ-amino acid building block synthesis, procedure of SPPS, peptide cleavage and purification are also summarized in detail. Chapter five starts with the background unnatural amino acids and foldamers. Then our design based on natural peptide S597 with our sulfono-γ-amino acid to mimic the sequence of site 1 or replacing natural amino acids with our sulfono-γ-amino acid are discussed. At the end of each chapter, NMR, Q-TOF, ESI-MS, and LC-MS data are attached.
Scholar Commons Citation
Wang, Yafeng, "The discovery of first RET PROTAC with in vivo activity" (2024). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/10574
