Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6
Open accessAbstract
The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.
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BI-3802 reduces BCL6 protein levels, resulting in de-repression of BCL6 target genes.
“Bi-3802 demonstrated potential by reducing Bcl6 protein levels, resulting in the de-repression of Bcl6 target genes (Kerres et al. 2017).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Kerres et al. 2017
BI-3802 was discovered through a high-throughput screen designed to identify compounds that inhibit BCL6's interaction with corepressors.
“Another serendipitous degrader, Bi-3802, was discovered through a high-throughput screen designed to identify compounds that could inhibit Bcl6's interaction with corepressors (Kerres et al. 2017).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Kerres et al. 2017
Screens for novel BCL6 inhibitors led to the identification of small molecules that unexpectedly induce BCL6 degradation, including BI-3802.
“Screens for novel BCL6 inhibitors led to the identification of small molecules that unexpectedly induce BCL6 degradation, including BI-38026.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [6]
BI-3802 induces rapid ubiquitination and degradation of BCL6.
“BI-3802 induces rapid ubiquitination and degradation of BCL6, resulting in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines, comparable to a genetic knock-out21, and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders5,6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [6]
BI-3802 binds the BTB domain of BCL6.
“BI-3802 is a small molecule that binds the BTB domain of the oncogenic transcription factor BCL6 and results in proteasomal degradation6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [6]
BI-3802 results in proteasomal degradation of BCL6.
“BI-3802 is a small molecule that binds the BTB domain of the oncogenic transcription factor BCL6 and results in proteasomal degradation6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [6]
The effects of BI-3802 are comparable to a genetic knock-out and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders.
“BI-3802 induces rapid ubiquitination and degradation of BCL6, resulting in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines, comparable to a genetic knock-out21, and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders5,6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [6]
BI-3802 results in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines.
“BI-3802 induces rapid ubiquitination and degradation of BCL6, resulting in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines, comparable to a genetic knock-out21, and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders5,6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [6]
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 [6]
CAR T cells are highly efficacious in patients with B cell malignancies but can cause severe T cell hyperactivation-related toxicities.
“For example, chimeric antigen receptor (CAR) T cells are highly efficacious in patients with B cell malignancies but can cause severe T cell hyperactivation-related toxicities190.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [190]
BI-3802, by degrading Bcl-6 via the ubiquitin proteasome system, displayed stronger de-repression of target genes than Bcl-6 inhibitors and demonstrated antiproliferative effects in several DLBCL cell lines.
“By degrading Bcl-6 via the UPS, BI-3802 displayed stronger de-repression of target genes than Bcl-6 inhibitors and demonstrated antiproliferative effects in several DLBCL cell lines [73].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [73]
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Polymerization of ZBTB transcription factors regulates chromatin occupancy
Park, P. M. C., Park, J., Brown, J., Hunkeler, M., Roy Burman, S. S., Donovan, K. A., Yoon, H., Nowak, R. P., Słabicki, M., Ebert, B. L., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.06.010 · Cited by 22 · see citing works
“5,6 Pre-existing surface complementarity between homodimers of BCL6’s BTB domain (BCL6 BTB ) is enhanced by the dimethylpiperidine moiety of BI-3802 making contacts across the interface and increasing the affinity between BCL6 BTB dimers.”
Chikada, H., Ida, K., Nishikawa, Y., Inagaki, Y., & Kamiya, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-66539-z · Cited by 17 · see citing works
From serendipity to strategy: molecular glue degraders in cancer therapeutics
Darling, S., Bajrami, I., & West, S. C. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2564068 · Cited by 10 · see citing works
“Bi-3802 demonstrated potential by reducing Bcl6 protein levels, resulting in the de-repression of Bcl6 target genes (Kerres et al. 2017). the anti-proliferative effects observed in lymphoma models closely mirrored genetic BCL6 deletion, surpassing the efficacy of non-degrading Bcl6 inhibitors such…”
- Authors
- Kerres, N., Steurer, S., Schlager, S., Bader, G., Berger, H., Caligiuri, M., Dank, C., Engen, J. R., Ettmayer, P., Fischerauer, B., Flotzinger, G., Gerlach, D., Gerstberger, T., Gmaschitz, T., Greb, P., Han, B., Heyes, E., Iacob, R. E., Kessler, D., Kölle, H., Lamarre, L., Lancia, D. R., Lucas, S., Mayer, M., Mayr, K., Mischerikow, N., Mück, K., Peinsipp, C., Petermann, O., Reiser, U., Rudolph, D., Rumpel, K., Salomon, C., Scharn, D., Schnitzer, R., Schrenk, A., Schweifer, N., Thompson, D., Traxler, E., Varecka, R., Voss, T., Weiss-Puxbaum, A., Winkler, S., Zheng, X., Zoephel, A., Kraut, N., McConnell, D., Pearson, M., & Koegl, M.
- Affiliations
- Boehringer Ingelheim (Austria) (AT)
- Forma Therapeutics (United States) (US)
- Northeastern University (US)
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Koegl, Manfred
- ORCID
- Schlager, Stefanie
- Bader, Gerd
- Dank, Christian
- Engen, John R.
- Gerlach, Daniel
- Gerstberger, Thomas
- Greb, Peter
- Heyes, Elizabeth
- Iacob, Roxana E.
- Kessler, Dirk
- Lancia, David R.
- Lucas, Simon
- Mayer, Moriz
- Mayr, Katharina
- Rudolph, Dorothea
- Rumpel, Klaus
- Scharn, Dirk
- Schweifer, Norbert
- Zheng, Xiaozhang
- Zoephel, Andreas
- Kraut, Norbert
- McConnell, Darryl
- Pearson, Mark
- Koegl, Manfred
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 20
- Issue
- 12
- Pages
- 2860-2875
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2755848776
- Cited by
- 207
- References
- 59
- Citations by year
- 2026: 17 · 2025: 38 · 2024: 22 · 2023: 22 · 2022: 35 · 2021: 33 · 2020: 22 · 2019: 10 · 2018: 7 · 2017: 1
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Wirschaftsagentur Wien
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- BCL6, protein degradation, ubiquitination, BTB domain, structure-based drug design, diffuse large B-cell lymphoma, transcriptional repression, antiproliferative activity
- MeSH terms
- Protein Domains, DNA, Humans, Kinetics, Models, Molecular, Protein Binding, Pyrimidines, Structure-Activity Relationship, Gene Expression Regulation, Neoplastic, Inhibitory Concentration 50, Cell Line, Tumor, Proteasome Endopeptidase Complex, Cell Proliferation, Proto-Oncogene Proteins c-bcl-6, Ubiquitination, HEK293 Cells, Proteolysis
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