Development of Protein Degraders Inspired by Chemical Modifications

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.

Name thesis:degree_name

M.S., Chemistry and Chemical Biology

Level thesis:degree_level

Master of Science

Discipline thesis:degree_discipline

Chemistry and Chemical Biology

Grantor

Cornell University

Year dc:date.issued

2025

Author dc:creator

• Ku, Ting-Chieh

Committee member dc:contributor.committeemember

• Yasuda, Saki

Language dc:language.iso

en

DOI

https://doi.org/10.7298/jyyd-nc38

Dc Identifier Other

ProQuest Submission ID: 12625
ProQuest Publication ID: 32395465

OAI identifier oai:identifier

oai:ecommons.cornell.edu:1813/120992