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Expanding the Targeted Protein Degradation Toolbox: Investigation of Molecular Mechanisms for the Degradation of Intracellular Proteins
Expanding the Targeted Protein Degradation Toolbox: Investigation of Molecular Mechanisms for the Degradation of Intracellular Proteins
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104640
- ISBN
- 9798280750203
- DDC
- 615
- 저자명
- Tandon, Ira.
- 서명/저자
- Expanding the Targeted Protein Degradation Toolbox: Investigation of Molecular Mechanisms for the Degradation of Intracellular Proteins
- 발행사항
- [Sl] : The University of Wisconsin - Madison, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 171 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Tang, Weiping.
- 학위논문주기
- Thesis (Ph.D.)--The University of Wisconsin - Madison, 2025.
- 초록/해제
- 요약In this work, we present novel contributions to the field of targeted protein degradation (TPD). We explore three areas of TPD: Proteolysis Targeting Chimeras (PROTACs), Autophagy-Tethering Chimeras (ATTECs), and Molecular Glue Degraders (MGDs). In the first section, we report our investigation and characterization of a dual degrader PROTAC that targets MDM2 and GSPT1/2. We also explore the use of novel E3 ligase ligands to degrade MDM2. In the second section of this work, we report our efforts to validate a TRIM24 PROTAC as well as the discovery of our own, more potent TRIM24 degrader. Next, we present our investigation of ATTECs and the utility of LC3B as an effector of autophagy-mediated TPD. Our findings suggest that the reported LC3B ligand does not interact with LC3B and may induce a degradation phenotype by other means. In the fifth chapter, we return our focus to PROTAC development focused on the target BTK. Herein, we report the development and characterization of novel BTK PROTACs that utilize an achiral ligand and a benzimidazole ligand for the recruitment of the E3 ligase CRBN. Lastly, we briefly discuss our foray into target-focused discovery of MGDs. In particular, we focus on MDM2 and BTK as targets and identify some MDM2-targeting compounds with unique activity that warrant further investigation.Overall, this work reports the novel activity of a previously reported MDM2 degrader as well as novel and effective PROTACs for TRIM24 and BTK. We also discuss our efforts to rationally design and study ATTECs and MGDs.
- 일반주제명
- Pharmacology
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 키워드
- Achiral ligand
- 키워드
- Novel activity
- 기타저자
- The University of Wisconsin - Madison Molecular & Cellular Pharmacology
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202104640
■006m o d
■007cr#unu||||||||
■020 ▼a9798280750203
■035 ▼a(MiAaPQ)AAI32113938
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a615
■1001 ▼aTandon, Ira.
■24510▼aExpanding the Targeted Protein Degradation Toolbox: Investigation of Molecular Mechanisms for the Degradation of Intracellular Proteins
■260 ▼a[Sl]▼bThe University of Wisconsin - Madison▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a171 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Tang, Weiping.
■5021 ▼aThesis (Ph.D.)--The University of Wisconsin - Madison, 2025.
■520 ▼aIn this work, we present novel contributions to the field of targeted protein degradation (TPD). We explore three areas of TPD: Proteolysis Targeting Chimeras (PROTACs), Autophagy-Tethering Chimeras (ATTECs), and Molecular Glue Degraders (MGDs). In the first section, we report our investigation and characterization of a dual degrader PROTAC that targets MDM2 and GSPT1/2. We also explore the use of novel E3 ligase ligands to degrade MDM2. In the second section of this work, we report our efforts to validate a TRIM24 PROTAC as well as the discovery of our own, more potent TRIM24 degrader. Next, we present our investigation of ATTECs and the utility of LC3B as an effector of autophagy-mediated TPD. Our findings suggest that the reported LC3B ligand does not interact with LC3B and may induce a degradation phenotype by other means. In the fifth chapter, we return our focus to PROTAC development focused on the target BTK. Herein, we report the development and characterization of novel BTK PROTACs that utilize an achiral ligand and a benzimidazole ligand for the recruitment of the E3 ligase CRBN. Lastly, we briefly discuss our foray into target-focused discovery of MGDs. In particular, we focus on MDM2 and BTK as targets and identify some MDM2-targeting compounds with unique activity that warrant further investigation.Overall, this work reports the novel activity of a previously reported MDM2 degrader as well as novel and effective PROTACs for TRIM24 and BTK. We also discuss our efforts to rationally design and study ATTECs and MGDs.
■590 ▼aSchool code: 0262.
■650 4▼aPharmacology
■650 4▼aCellular biology
■650 4▼aMolecular biology
■653 ▼aMolecular Glue Degraders
■653 ▼aTargeted protein degradation
■653 ▼aAchiral ligand
■653 ▼aNovel activity
■690 ▼a0419
■690 ▼a0379
■690 ▼a0307
■71020▼aThe University of Wisconsin - Madison▼bMolecular & Cellular Pharmacology.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0262
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358301▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
