서브메뉴
검색
Development of Regulated Induced-Proximity Targeting Chimeras (RIPTACs) for Cancer Specific Proteins
Development of Regulated Induced-Proximity Targeting Chimeras (RIPTACs) for Cancer Specific Proteins
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260311091512.5
- ISBN
- 9798286445479
- DDC
- 572.6
- 서명/저자
- Development of Regulated Induced-Proximity Targeting Chimeras (RIPTACs) for Cancer Specific Proteins / Jose Ignacio Vergara Panzone
- 발행사항
- [Sl] : Yale University, 2025
- 형태사항
- 1 electronic resource (269 pages)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisors: Crews, Craig M. Committee members: Malaker, Stacy A.; Crawford, Jason M.
- 학위논문주기
- - Ph.D. : Yale University, 2025.
- 초록/해제
- 요약RIPTACs are heterobifunctional small molecules that induce the formation of a ternary complex between a cancer-specific target protein and a pan-essential effector protein to elicit cell-type selective cytotoxicity. Herein, we describe the development of RIPTACs designed to target the cancer-specific oncogenic driver ALK while inhibiting CDKs. Despite achieving ternary complex formation in vitro, ALK-CDK RIPTACs were found to induce off-target ternary complexes that compromised selectivity between ALK-expressing cells and the negative control cell line. To elucidate the nuances of the RIPTAC modality, we studied a RIPTAC, HLDA-6623, that induced formation of a ternary complex between two previously validated protein partners: the oncogenic driver BCL6 and the pan-essential effector protein BRD4. We hypothesized that a RIPTAC mechanism is also operative in the cytotoxic phenotype caused by BCL6-BRD4 TCIPs (transcriptional chemical inducers of proximity), a platform capable of inducing transcriptional rewiring to induce cell death. Transcriptional chemical inducers of proximity recruit BCL6 and BRD4 to differentially express pro-apoptotic genes. Using a structurally distinct BCL6-BRD4 RIPTAC, HLDA-6623, we observed that transcriptional rewiring occurred exclusively in cells expressing BCL6WT but was absent in cells expressing a DNA-binding mutant BCL6DBM. However, HLDA-6623 enhanced cytotoxicity in both the BCL6WT and BCL6DBM cell lines, suggesting that the RIPTAC mechanism, and not transcriptional rewiring, drives the antiproliferative phenotype of these heterobifunctional small molecules.
- 언어주기
- English
- 일반주제명
- Organic chemistry
- 일반주제명
- Chemistry
- 일반주제명
- Cellular biology
- 일반주제명
- Oncology
- 일반주제명
- Biochemistry
- 키워드
- Ternary complex
- 기타저자
- Yale University Chemistry
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008260311s2025 us eng d■001000017356739
■00520260311091512.5
■006m o d
■007cr|nu||||||||
■020 ▼a9798286445479
■040 ▼aMiAaPQD▼beng▼cMiAaPQD▼erda
■082 ▼a572.6
■1001 ▼aVergara Panzone, Jose Ignacio▼eauthor.
■24510▼aDevelopment of Regulated Induced-Proximity Targeting Chimeras (RIPTACs) for Cancer Specific Proteins ▼cJose Ignacio Vergara Panzone
■260 ▼a[Sl]▼bYale University▼c2025
■264 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a1 electronic resource (269 pages)
■336 ▼atext▼btxt▼2rdacontent
■337 ▼acomputer▼bc▼2rdamedia
■338 ▼aonline resource▼bcr▼2rdacarrier
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisors: Crews, Craig M. Committee members: Malaker, Stacy A.; Crawford, Jason M.
■5021 ▼bPh.D.▼cYale University▼d2025.
■520 ▼aRIPTACs are heterobifunctional small molecules that induce the formation of a ternary complex between a cancer-specific target protein and a pan-essential effector protein to elicit cell-type selective cytotoxicity. Herein, we describe the development of RIPTACs designed to target the cancer-specific oncogenic driver ALK while inhibiting CDKs. Despite achieving ternary complex formation in vitro, ALK-CDK RIPTACs were found to induce off-target ternary complexes that compromised selectivity between ALK-expressing cells and the negative control cell line. To elucidate the nuances of the RIPTAC modality, we studied a RIPTAC, HLDA-6623, that induced formation of a ternary complex between two previously validated protein partners: the oncogenic driver BCL6 and the pan-essential effector protein BRD4. We hypothesized that a RIPTAC mechanism is also operative in the cytotoxic phenotype caused by BCL6-BRD4 TCIPs (transcriptional chemical inducers of proximity), a platform capable of inducing transcriptional rewiring to induce cell death. Transcriptional chemical inducers of proximity recruit BCL6 and BRD4 to differentially express pro-apoptotic genes. Using a structurally distinct BCL6-BRD4 RIPTAC, HLDA-6623, we observed that transcriptional rewiring occurred exclusively in cells expressing BCL6WT but was absent in cells expressing a DNA-binding mutant BCL6DBM. However, HLDA-6623 enhanced cytotoxicity in both the BCL6WT and BCL6DBM cell lines, suggesting that the RIPTAC mechanism, and not transcriptional rewiring, drives the antiproliferative phenotype of these heterobifunctional small molecules.
■546 ▼aEnglish
■590 ▼aSchool code: 0265
■650 4▼aOrganic chemistry
■650 4▼aChemistry
■650 4▼aCellular biology
■650 4▼aOncology
■650 4▼aBiochemistry
■653 ▼aAntiproliferative phenotype
■653 ▼aHeterobifunctional molecules
■653 ▼aTernary complex
■653 ▼aPan-essential effector protein
■7102 ▼aYale University▼bChemistry.▼edegree granting institution.
■7201 ▼aCrews, Craig M.▼edegree supervisor.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17356739▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
