BCL6 degrader
BI-3802
BI-3802 is a highly potent B-cell lymphoma 6 (BCL6) inhibitor. It inhibits the interaction of the BTB/POZ domain of BCL6 with several co-repressors in vitro as well as in a cellular context. In addition, BI-3802 was found to be a potent and efficacious degrader of the BCL6 protein in many DLBCL cell lines1. Its good permeability and unprecedented protein degradation effects make this compound an ideal tool to study BCL6 biology in vitro.
Concept: Mikołaj Słabicki, Hojong Yoon, Jonas Koeppel, Animation: JumpStartVideo.net11
More information
B-cell lymphoma 6 (BCL6) functions as a transcriptional repressor that binds specific DNA sequences via its Zn-fingers and recruits transcriptional co-repressors (e.g. BCOR, SMRT, NCOR) by its BTB/POZ domain2. BCL6 is essential for the germinal center (GC) reaction3. It represses a broad set of genes that are required to sustain mutagenic activity without activating the DNA damage response or apoptosis4. BCL6 also prevents maturation to plasma or memory cells and helps to maintain a de-differentiated state. Its expression must be switched off to allow the B-cell to exit the GC cycle and differentiate. BCL6 is a known oncogenic driver and frequently overexpressed in DLBCL5,6.
BCL6-BTB dimer with BI-3802, as observed by X-ray1.
BI-3802 binds at the interface of two monomers (monomers are shown in green and grey).
BI-3802 displays an IC50 ≤ 3 nM in a BCL6::BCOR ULight TR-FRET assay and degrades BCL6 protein with a DC50 of 20 nM (in SU-DHL-4 cell lines)1.
It also inhibits the BCL6::Co-repressor complex formation with an IC50 of 43 nM.
It is recommended to store and use 1 mM DMSO stock solutions of BI-3802 for all in vitro experiments.
| PROBE NAME / NEGATIVE CONTROL | BI-3802 | BI-5273 |
| MW [Da, free base]a | 484.9 | 500.0 |
| BCL6::BCOR ULight TR-FRET (IC50) [nM]b | ≤ 3 | 10162 |
| BCL6::NCOR LUMIER (IC50) [nM] | 43 | n.a. |
| BCL6 protein degradation (DC50) [nM]c | 20 | Inactive |
aFor the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs.
bWith affinities of approximately 3 nM, the assay wall of this assay is reached, limiting the accuracy of the biochemical assay.
bIn SU-DHL-4 cells
| PROBE NAME / NEGATIVE CONTROL | BI-3802 | BI-5273 |
| log D @ pH 11 | 4.6 | 1.6 |
| Solubility @ pH 6.8 [µg/mL] | <1 | 84 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 8.5 | 22 |
| Caco-2 efflux ratio | 0.4 | 0.6 |
| Human hepatocyte clearance [% QH] | 56 | n.a. |
| Plasma Protein Binding human [%] | 99.9 | n.a. |
BI-3802 showed poor bioavailability after p.o. administration in mice (see table).
| BI-3802 | MOUSE | |
|---|---|---|
| AUC [nM/h] | 1860 | 4650 |
| Cmax [nM] | 193 | 599 |
| tmax [h] | 2 | 4.6 |
ai.v. dose: 10 mg/kg
bp.o. dose: 100 mg/kg
BI-5273 is a close analog of BI-3802 which binds only very weakly to the BCL6 BTB domain (IC50 ~ 10 µM) and does not induce protein degradation.
BI-5273, negative control
| SELECTIVITY DATA AVILABLE | BI-3802 | BI-5273 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BCL6-degr_BI-3802_selectivityData_0.xlsx
BI-5273_selectivityData.xlsx
The X-ray crystal structure of BCL6 in complex with BI-3802 is available (PDB code: 5MW2)1.
Several small molecule BCL6 inhibitors have been published recently7,8,9,10. None of those is described as a BCL6 protein degrader.
BI-3802 is a single digit nanomolar BCL6::Co-repressor inhibitor which induces efficacious BCL6 protein degradation in several DLBCL cell lines.
Chemically induced degradation of the oncogenic transcription factor BCL6
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.
Cell Rep. 2017, 20, 2860-2875.
Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells
Basso K., Saito M., Sumazin P., Margolin A. A., Wang K., Lim W. K., Kitagawa Y., Schneider C., Alvarez M. J., Califano A., Dalla-Favera R.
Blood 2010, 115, 975-984.
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma
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. Jr., Melnick A. M.
J. Clin. Invest. 2016, 126, 3351-3362.
Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
McCoull W., Abrams R. D., Anderson E., Blades K., Barton P., Box M., Burgess J., Byth K., Cao Q., Chuaqui C., Carbajo R. J., Cheung T., Code E., Ferguson A. D., Fillery S., Fuller N. O., Gangl E., Gao N., Grist M., Hargreaves D., Howard M. R., Hu J., Kemmitt P. D., Nelson J. E., O'Connell N., Prince D. B., Raubo P., Rawlins P. B., Robb G. R., Shi J., Waring M. J., Whittaker D., Wylot M., Zhu X.
J. Med. Chem. 2017, 60, 4386-4402.
Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design
Yasui T., Yamamoto T., Sakai N., Asano K., Takai T., Yoshitomi Y., Davis M., Takagi T., Sakamoto K., Sogabe S., Kamada Y., Lane W., Snell G., Iwata M., Goto M., Inooka H., Sakamoto J. I., Nakada Y., Imaeda Y.
Bioorg. Med. Chem. 2017, 25, 4876-4886.
Video Credits
Mikołaj Słabicki, Jonas Koeppel Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany Hojong Yoon Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
When you plan a publication, please use the following acknowledgement:
BI-3802 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.