2026-09-19T16:19:22Zhttps://ecommons.cornell.edu/server/oai/requestoai:ecommons.cornell.edu:1813/1209922026-05-15T17:53:43Zcom_1813_35col_1813_47
Ku, Ting-Chieh
Zax, David
Yasuda, Saki
2026-04-02T19:05:24Z
2025-12
ProQuest Submission ID: 12625
ProQuest Publication ID: 32395465
https://hdl.handle.net/1813/120992
https://doi.org/10.7298/jyyd-nc38
17423333
112 pages
The studies presented in this thesis focus on the development of the chemical modification-inspired dehydroalanine (Dha)-based protein degraders, including their synthesis, optimization, mechanistic elucidation, and transferability assessment. First, a Dha-based bromodomain-containing protein 4 (BRD4) degrader was synthesized and demonstrated to induce consistent attenuation of BRD4 levels at micromolar potency. Subsequent optimization revealed that a spacer is not required for Dha-based degrader design, indicating that Dha itself can function as the minimal E3 ligase-recruiting handle and that tighter ternary complex formation is favored. Mechanistic elucidation via inhibitor screening confirmed that the Dha-based degrader operates through the ubiquitin-proteasome system by recruiting a Cullin-RING E3 ligase. Lastly, transferability studies showed that the incorporation of the Dha handle into phosphodiesterase type-5 (PDE5) and androgen receptor (AR) binders also promoted target degradation, highlighting the potential of the Dha handle as a versatile scaffold for E3 ligase recruitment toward diverse disease-relevant proteins.
2028-01-08
en
Development of Protein Degraders Inspired by Chemical Modifications
dissertation or thesis
application/pdf
Chemistry and Chemical Biology
Cornell University
Master of Science
M.S., Chemistry and Chemical Biology
https://hdl.handle.net/1813/59810.2
Publication
Cornell Theses and Dissertations
Ku, Ting-Chieh
5893a6ea-7af3-41d7-abc6-04bcd26ab5df
embargo
embargo
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<Abstract>The studies presented in this thesis focus on the development of the chemical modification-inspired dehydroalanine (Dha)-based protein degraders, including their synthesis, optimization, mechanistic elucidation, and transferability assessment. First, a Dha-based bromodomain-containing protein 4 (BRD4) degrader was synthesized and demonstrated to induce consistent attenuation of BRD4 levels at micromolar potency. Subsequent optimization revealed that a spacer is not required for Dha-based degrader design, indicating that Dha itself can function as the minimal E3 ligase-recruiting handle and that tighter ternary complex formation is favored. Mechanistic elucidation via inhibitor screening confirmed that the Dha-based degrader operates through the ubiquitin-proteasome system by recruiting a Cullin-RING E3 ligase. Lastly, transferability studies showed that the incorporation of the Dha handle into phosphodiesterase type-5 (PDE5) and androgen receptor (AR) binders also promoted target degradation, highlighting the potential of the Dha handle as a versatile scaffold for E3 ligase recruitment toward diverse disease-relevant proteins.</Abstract>
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