Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders
Open accessAbstract
Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein–protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.
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BI-3802, as well as structurally related bioavailable analogs, have markedly increased activity against lymphoma cells compared to BI-3812, likely due to the combined effects of inhibiting co-activator binding, sequestering BCL6 into foci, and degrading BCL6.
“BI-3802, as well as structurally related bioavailable analogs29, have markedly increased activity against lymphoma cells compared to BI-38126, which is likely due to the combined effects of inhibiting co-activator binding, sequestering BCL6 into foci, and degrading BCL6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [29]
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- Authors
- Bellenie, B. R., Cheung, K.-M. J., Varela, A., Pierrat, O. A., Collie, G. W., Box, G. M., Bright, M. D., Gowan, S., Hayes, A., Rodrigues, M. J., Shetty, K. N., Carter, M., Davis, O. A., Henley, A. T., Innocenti, P., Johnson, L. D., Liu, M., de Klerk, S., Le Bihan, Y.-V., Lloyd, M. G., McAndrew, P. C., Shehu, E., Talbot, R., Woodward, H. L., Burke, R., Kirkin, V., van Montfort, R. L. M., Raynaud, F. I., Rossanese, O. W., & Hoelder, S.
- Affiliations
- Institute of Cancer Research (GB)
- The Institute of Cancer Research , , ,
- Corresponding author
- Hoelder, Swen
- ORCID
- Bellenie, Benjamin R.
- Collie, Gavin W.
- Bright, Michael D.
- Hayes, Angela
- Rodrigues, Matthew J.
- Shetty, Kartika N.
- Carter, Michael
- Davis, Owen A.
- Innocenti, Paolo
- Liu, Manjuan
- Le Bihan, Yann-Vaï
- Talbot, Rachel
- Woodward, Hannah L.
- Burke, Rosemary
- Kirkin, Vladimir
- Raynaud, Florence I.
- Rossanese, Olivia W.
- Hoelder, Swen
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-04-10
- Volume
- 63
- Issue
- 8
- Pages
- 4047-4068
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC7184563
- OpenAlex
- W3015876543
- Cited by
- 74
- References
- 25
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 11 · 2023: 10 · 2022: 21 · 2021: 12 · 2020: 1
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Cancer Research UK (C309/A11566)
- Cancer Research Technology (NA)
- European investment fund (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- BCL6, benzimidazolone, protein degradation, protein-protein interaction inhibitors, diffuse large B-cell lymphoma, germinal center B-cell lymphoma, pharmacokinetic optimization, oral bioavailability, lymphoma xenografts, targeted protein degradation
- MeSH terms
- Animals, Benzimidazoles, Female, Humans, Male, Mice, Inbred BALB C, Microsomes, Liver, Drug Delivery Systems, Mice, SCID, Rats, Sprague-Dawley, Protein Structure, Tertiary, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Rats, Proto-Oncogene Proteins c-bcl-6, Drug Discovery
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