{"id":{"repo_id":"cornell","oai_identifier":"oai:ecommons.cornell.edu:1813/120992"},"canonical_url":"https://search.dev.ndltd.org/etd/cornell/oai:ecommons.cornell.edu:1813/120992","repository":{"repo_id":"cornell","name":"Cornell University","base_url":"https://ecommons.cornell.edu/server/oai/request"},"display":{"title":"Development of Protein Degraders Inspired by Chemical Modifications","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_html":"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_has_math":false,"creators":["Ku, Ting-Chieh"],"institution":"Cornell University","degree_name":"M.S., Chemistry and Chemical Biology","degree_level":"Master of Science","degree_discipline":"Chemistry and Chemical Biology","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":["Yasuda, Saki"],"year":2025,"date_issued":"2025-12","date_published":"2025-12","updated_at":"2026-07-24T01:49:08Z","subjects":[],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7298/jyyd-nc38"],"render_values":[{"text":"https://doi.org/10.7298/jyyd-nc38","href":"https://doi.org/10.7298/jyyd-nc38","code":true}]},{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["ProQuest Submission ID: 12625","ProQuest Publication ID: 32395465"],"render_values":[{"text":"ProQuest Submission ID: 12625","href":null,"code":true},{"text":"ProQuest Publication ID: 32395465","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1813/120992","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Yasuda, Saki"]},{"key":"dc:creator","label":"Author","values":["Ku, Ting-Chieh"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-04-02T19:05:24Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-12"]},{"key":"dc:type","label":"Dc Type","values":["dissertation or thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry and Chemical Biology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Master of Science"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M.S., Chemistry and Chemical Biology"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Cornell University"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7298/jyyd-nc38"]},{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["ProQuest Submission ID: 12625","ProQuest Publication ID: 32395465"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1813/120992"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["112 pages"]},{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Development of Protein Degraders Inspired by Chemical Modifications"]}]}],"canonical_facts":{"dc:contributor.committeemember":["Yasuda, Saki"],"dc:creator":["Ku, Ting-Chieh"],"dc:date.accessioned":["2026-04-02T19:05:24Z"],"dc:date.issued":["2025-12"],"dc:description":["112 pages"],"dc:description.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."],"dc:format.mimetype":["application/pdf"],"dc:identifier.doi":["https://doi.org/10.7298/jyyd-nc38"],"dc:identifier.other":["ProQuest Submission ID: 12625","ProQuest Publication ID: 32395465"],"dc:identifier.uri":["https://hdl.handle.net/1813/120992"],"dc:language.iso":["en"],"dc:title":["Development of Protein Degraders Inspired by Chemical Modifications"],"dc:type":["dissertation or thesis"],"thesis:degree_discipline":["Chemistry and Chemical Biology"],"thesis:degree_level":["Master of Science"],"thesis:degree_name":["M.S., Chemistry and Chemical Biology"],"thesis:institution_name":["Cornell University"]},"updated_at":"2026-07-24T01:49:08Z"}