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Expanding the Toolbox of E3 Ligases for Targeted Protein Degradation
Expanding the Toolbox of E3 Ligases for Targeted Protein Degradation
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103117
- ISBN
- 9798315799511
- DDC
- 540
- 서명/저자
- Expanding the Toolbox of E3 Ligases for Targeted Protein Degradation
- 발행사항
- [Sl] : Northwestern University, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 164 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Zhang, Xiaoyu.
- 학위논문주기
- Thesis (Ph.D.)--Northwestern University, 2025.
- 초록/해제
- 요약Small-molecule drug discovery has conventionally revolved around the rational design of candidates for binding to functional hydrophobic pockets on a target surface. However, many targets implicated in complex disease states such as cancer lack these binding sites, rendering them "undruggable" and elusive to therapeutic intervention. It is estimated that 85% of disease targets fall into this category, leading to a critical unmet need for the development of new drug modalities to broaden the scope of treatable human disease. Targeted protein degradation (TPD) has emerged as a disruptive therapeutic paradigm with great potential to expand the druggable target space by exploiting the cellular degradation machinery, the ubiquitin-proteasome system (UPS), to induce the degradation of a target protein.Degraders induce a noncanonical interaction between a covalently recruited E3 ligase and a protein of interest, leading to the proximity-induced ubiquitination and subsequent degradation of the target. Of the over 680 known E3 ubiquitin ligases, only a dozen or so to date have been employed for this approach. There is a clear need to identify additional E3 ligases that can be harnessed for TPD, to accommodate a broad range of therapeutically relevant targets with differential localization and expression. This work delineates several efforts to discover chemically ligandable E3 ligases to support targeted protein degradation. Chapter 1 provides a terse overview of ubiquitin biology, the TPD field, and advanced proteomic techniques critical to the work herein. Chapter 2 details the development, validation, and implementation of a pooled CRISPR transcriptional activation screen covering all known E3 ubiquitin ligases to identify FBXO22 as an E3 ligase supporting targeted protein degradation. FBXO22 is broadly overexpressed across cancers and can be recruited to induce the degradation of various intracellular protein targets. Chapter 3 describes the phenotypic screening-based discovery of a recruiter for the FBXW7 R465C mutant E3 ligase, expressed in many stomach and colorectal cancers. The identified recruiter is selective for the R465C mutant over wild-type FBXW7, opening new possibilities for cancer-specific degrader therapies. Overall, targeted protein degradation holds great promise in broadening the scope of treatable human disease, and the work herein substantially contributes to the repertoire of effectors suitable for this purpose.
- 일반주제명
- Chemistry
- 일반주제명
- Oncology
- 일반주제명
- Pharmaceutical sciences
- 일반주제명
- Biochemistry
- 키워드
- Chemical biology
- 키워드
- Chemoproteomics
- 키워드
- E3 ligase
- 기타저자
- Northwestern University Chemistry
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■006m o d
■007cr#unu||||||||
■020 ▼a9798315799511
■035 ▼a(MiAaPQ)AAI31937389
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a540
■1001 ▼aBasu, Ananya Angela.▼0(orcid)0000-0002-1427-5326
■24510▼aExpanding the Toolbox of E3 Ligases for Targeted Protein Degradation
■260 ▼a[Sl]▼bNorthwestern University▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a164 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Zhang, Xiaoyu.
■5021 ▼aThesis (Ph.D.)--Northwestern University, 2025.
■520 ▼aSmall-molecule drug discovery has conventionally revolved around the rational design of candidates for binding to functional hydrophobic pockets on a target surface. However, many targets implicated in complex disease states such as cancer lack these binding sites, rendering them "undruggable" and elusive to therapeutic intervention. It is estimated that 85% of disease targets fall into this category, leading to a critical unmet need for the development of new drug modalities to broaden the scope of treatable human disease. Targeted protein degradation (TPD) has emerged as a disruptive therapeutic paradigm with great potential to expand the druggable target space by exploiting the cellular degradation machinery, the ubiquitin-proteasome system (UPS), to induce the degradation of a target protein.Degraders induce a noncanonical interaction between a covalently recruited E3 ligase and a protein of interest, leading to the proximity-induced ubiquitination and subsequent degradation of the target. Of the over 680 known E3 ubiquitin ligases, only a dozen or so to date have been employed for this approach. There is a clear need to identify additional E3 ligases that can be harnessed for TPD, to accommodate a broad range of therapeutically relevant targets with differential localization and expression. This work delineates several efforts to discover chemically ligandable E3 ligases to support targeted protein degradation. Chapter 1 provides a terse overview of ubiquitin biology, the TPD field, and advanced proteomic techniques critical to the work herein. Chapter 2 details the development, validation, and implementation of a pooled CRISPR transcriptional activation screen covering all known E3 ubiquitin ligases to identify FBXO22 as an E3 ligase supporting targeted protein degradation. FBXO22 is broadly overexpressed across cancers and can be recruited to induce the degradation of various intracellular protein targets. Chapter 3 describes the phenotypic screening-based discovery of a recruiter for the FBXW7 R465C mutant E3 ligase, expressed in many stomach and colorectal cancers. The identified recruiter is selective for the R465C mutant over wild-type FBXW7, opening new possibilities for cancer-specific degrader therapies. Overall, targeted protein degradation holds great promise in broadening the scope of treatable human disease, and the work herein substantially contributes to the repertoire of effectors suitable for this purpose.
■590 ▼aSchool code: 0163.
■650 4▼aChemistry
■650 4▼aOncology
■650 4▼aPharmaceutical sciences
■650 4▼aBiochemistry
■653 ▼aChemical biology
■653 ▼aChemoproteomics
■653 ▼aCompound screening
■653 ▼aE3 ligase
■653 ▼aProteolysis targeting chimeras
■653 ▼aTargeted protein degradation
■690 ▼a0485
■690 ▼a0992
■690 ▼a0487
■690 ▼a0572
■71020▼aNorthwestern University▼bChemistry.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0163
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357018▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
