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A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo
Open accessAbstract
The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.
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“Several peptide and small molecule inhibitors targeting BCL6 have shown efficacy in vivo, but only at high concentrations, which has limited their translation into clinical therapeutic agents13,14.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [13]
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“BCL6 is a promising drug target for non-Hodgkin lymphomas including diffuse large B cell lymphoma (DLBCL)13,14 and follicular lymphoma15.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [13]
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Metadata
- Authors
- Cerchietti, L. C., Ghetu, A. F., Zhu, X., Da Silva, G. F., Zhong, S., Matthews, M., Bunting, K. L., Polo, J. M., Farès, C., Arrowsmith, C. H., Yang, S. N., Garcia, M., Coop, A., MacKerell, A. D., Privé, G. G., & Melnick, A.
- Affiliations
- Cornell University (US)
- University of Maryland, Baltimore (US)
- Albert Einstein College of Medicine (US)
- University of Toronto (CA)
- Corresponding author
- MacKerell, Alexander D.
- Privé, Gilbert G.
- Melnick, Ari
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 17
- Issue
- 4
- Pages
- 400-411
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2858395
- OpenAlex
- W2018796139
- Cited by
- 288
- References
- 53
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 9 · 2023: 9 · 2022: 13 · 2021: 12 · 2020: 20 · 2019: 19 · 2018: 16 · 2017: 15 · 2016: 30 · 2015: 28 · 2014: 24 · 2013: 28 · 2012: 22
- FWCI
- 16.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- Funders
- Canadian Cancer Society
- Leukemia and Lymphoma Society
- National Cancer Institute (R01 CA104348)
- National Institutes of Health (HL082670, CA107331, CA120215)
- University of Maryland Foundation Inc.
- Chemotherapy Foundation
- Samuel Waxman Cancer Research Foundation
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- BCL6, diffuse large B-cell lymphoma, small molecule inhibitors, BTB domain, transcriptional repressor, computer-aided drug design, xenotransplantation, oncogenes
- MeSH terms
- Animals, Cell Division, Cell Survival, Humans, Mice, Inbred C57BL, Models, Molecular, Protein Conformation, Proto-Oncogene Proteins, Repressor Proteins, Transcription, Genetic, Zinc Fingers, Lymphoma, Large B-Cell, Diffuse, Crystallography, X-Ray, Mice
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