Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma
Open accessAbstract
Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.
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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 agents.
“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 [14]
BCL6 is a promising drug target for non-Hodgkin lymphomas including diffuse large B cell lymphoma and follicular lymphoma.
“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 [14]
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Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors
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An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas
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Facilitating the development of molecular glues: Opportunities from serendipity and rational design
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Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma
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- Authors
- Cardenas, M. G., Yu, W., Beguelin, W., Teater, M. R., Geng, H., Goldstein, R. L., Oswald, E., Hatzi, K., Yang, S.-N., Cohen, J., Shaknovich, R., Vanommeslaeghe, K., Cheng, H., Liang, D., Cho, H. J., Abbott, J., Tam, W., Du, W., Leonard, J. P., Elemento, O., Cerchietti, L., Cierpicki, T., Xue, F., MacKerell, A. D., & Melnick, A. M.
- Affiliations
- University of Maryland, Baltimore (US)
- University of California, San Francisco (US)
- Weill Cornell Medicine (US)
- University of Michigan (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-08-02
- Volume
- 126
- Issue
- 9
- Pages
- 3351-3362
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5004937
- OpenAlex
- W2505733981
- Cited by
- 176
- References
- 40
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 19 · 2023: 14 · 2022: 25 · 2021: 16 · 2020: 21 · 2019: 18 · 2018: 20 · 2017: 16 · 2016: 5
- FWCI
- 18.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Samuel Waxman Cancer Research Foundation
- Leukemia and Lymphoma Society
- Weill Cornell Medical College
- National Cancer Institute (R01CA194547)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- BCL6, small molecule inhibitors, germinal center, chromosomal translocation, lymphoma treatment
- MeSH terms
- Animals, Antineoplastic Agents, Doxorubicin, Drug Screening Assays, Antitumor, Humans, Indoles, Ligands, Male, Neoplasm Transplantation, Magnetic Resonance Spectroscopy, Protein Binding, Translocation, Genetic, Drug Design, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse, Mice, SCID, Thiazolidinediones, Cell Line, Tumor, Mice, Proto-Oncogene Proteins c-bcl-6, HEK293 Cells
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