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Journal article
Evaluation of the Small-molecule BRD4 Degrader CFT-2718 in Small-cell Lung Cancer and Pancreatic Cancer Models
Molecular cancer therapeutics, v 20(8), pp 1367-1377
01 Aug 2021
PMID: 34045230
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Targeted, catalytic degradation of oncoproteins using heterobi-functional small molecules is an attractive modality, particularly for hematologic malignancies, which are often initiated by aberrant transcription factors and are challenging to drug with inhibitors. BRD4, amember of the bromodomain and extraterminal family, is a core transcriptional and epigenetic regulator that recruits the P-TEFb complex, which includes Cdk9 and cyclin T, to RNA polymerase II (pol II). Together, BRD4 and CDK9 phosphorylate serine 2 (pSer2) of heptad repeats in the C-terminal domain of RPB1, the large subunit of pol II, promote transcriptional elongation. Small-molecule degraders of BRD4 have shown encouraging efficacy in preclinical models for several tumor types but less efficacy in other cancers including small-cell lung cancer (SCLC) and pancreatic cancer. Here, we evaluated CFT-2718, a new BRD4-targeting degrader with enhanced catalytic activity and in vivo properties. In vivo, CFT-2718 has significantly greater efficacy than the CDK9 inhibitor dinaciclib in reducing growth of the LX-36 SCLC patient-derived xenograft (PDX) model and performed comparably to dinaciclib in limiting growth of the PNX-001 pancreatic PDX model. In vitro, CFT-2718 reduced cell viability in four SCLC and two pancreatic cancer models. In SCLC models, this activity significantly exceeded that of dinaciclib; furthermore, CFT- 2718 selectively increased the expression of cleaved PARP, an indicator of apoptosis. CFT-2718 caused rapid BRD4 degradation and reduced levels of total and pSer2 RPB1 protein. These and other findings suggest that BRD-mediated transcriptional suppression merits further exploration in the setting of SCLC.
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Details
- Title
- Evaluation of the Small-molecule BRD4 Degrader CFT-2718 in Small-cell Lung Cancer and Pancreatic Cancer Models
- Creators
- Danlin Sun - Institute of Life Sciences, Jiangsu University, Jinkou District, Zhenjiang, Jiangsu, China.Anna S. Nikonova - Fox Chase Cancer CenterPeishan Zhang - Institute of Life Sciences, Jiangsu University, Jinkou District, Zhenjiang, Jiangsu, China.Alexander Y. Deneka - Fox Chase Cancer CenterMark E. Fitzgerald - C4 TherapeuticsRyan E. Michael - C4 TherapeuticsLinda Lee - C4 Therapeutics (United States)Anna C. Lilly - Drexel UniversityStewart L. Fisher - C4 TherapeuticsAndrew J. Phillips - C4 TherapeuticsChristopher G. Nasveschuk - C4 TherapeuticsDavid A. Proia - C4 TherapeuticsZhigang Tu - Institute of Life Sciences, Jiangsu University, Jinkou District, Zhenjiang, Jiangsu, China.Erica A. Golemis - Fox Chase Cancer Center
- Publication Details
- Molecular cancer therapeutics, v 20(8), pp 1367-1377
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 11
- Grant note
- P30 CA006927 / NCI Core Grant P50 DE030707 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA William Wikoff Smith Charitable Trust
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Engineering
- Web of Science ID
- WOS:000680862700005
- Scopus ID
- 2-s2.0-85111652601
- Other Identifier
- 991019168541904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology