BCL6 inhibitor
BI-3812
BI-3812 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 (IC50 ≤ 3 nM), as well as the formation of BCL6::Co-repressor complexes in a cellular context (IC50 = 40 nM)1. Its high potency and good permeability make it an attractive tool for testing hypotheses around BCL6 biology in vitro.
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 Diffuse large B-cell lymphoma (DLBCL)5,6.
BCL6-BTB dimer with BI-3802, as observed by X-ray1. BI-3802, a close analog of BI-3812, binds at the interface of two monomers (monomers are shown in green and grey)
BI-3812 displays an IC50 ≤ 3 nM in a BCL6::BCOR ULight TR-FRET assay.
| PROBE NAME / NEGATIVE CONTROL | BI-3812 | BI-5273 |
| MW [Da, free base]a | 558.0 | 500.0 |
| BCL6::BCOR ULight TR-FRET (IC50) [nM]b | ≤ 3 | 10162 |
| BCL6::NCOR LUMIER in cells (IC50) [nM] | 40 | n.a. |
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.
| PROBE NAME / NEGATIVE CONTROL | BI-3812 | BI-5273 |
| log D @ pH 11 | 2.2 | 1.6 |
| Solubility @ pH 6.8 [µg/mL] | <1 | 84 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 2.8 | 22 |
| Caco-2 efflux ratio | 14 | 0.6 |
| Plasma Protein Binding human [%] | 96.9 | n.a. |
BI-5273 is a close analog of BI-3812 which binds only very weakly to the BCL6 BTB domain (IC50 ~ 10 µM).
BI-5273, which serves as a negative control
The intracellular selectivity profile was determined for the close analog BI-3802. For BI-3802, BCL6 was confirmed as the major target of this compound in DLBCL cells1.
| SELECTIVITY DATA AVILABLE | BI-3812 | BI-5273 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-3812_selectivityData.xlsx
BI-5273_selectivityData_0.xlsx
Not available. However, the X-ray structure with the close analog BI-3802 (PDB code: 5MW2) was solved at Boehringer Ingelheim.
Several small molecule BCL6 inhibitors have been published recently7,8,9,10.
BI-3812 is a single digit nanomolar BCL6::Co-repressor inhibitor which also inhibits the BCL6::Co-repressor complex formation in cells.
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.
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When you plan a publication, please use the following acknowledgement:
BI-3812 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.