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BCL6 transcription repressor

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2957

Nomenclature: BCL6 transcription repressor

Family: BTB (POZ) domain containing TFs

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 706 3q27.3 BCL6 BCL6 transcription repressor
Mouse - 707 16 15.26 cM Bcl6 B cell leukemia/lymphoma 6
Rat - 707 11q23 Bcl6 BCL6, transcription repressor
Gene and Protein Information Comments
Alternatively spliced transcript variants encoding different protein isoforms have been found for the human gene.
Previous and Unofficial Names Click here for help
BCL6 | BCL6, transcription repressor | B-cell CLL/lymphoma 6 | B cell CLL/lymphoma 6 | LAZ3 | ZBTB27 | zinc finger protein 51 | ZNF51
Database Links Click here for help
Alphafold P41182 (Hs), P41183 (Mm)
ChEMBL Target CHEMBL4105786 (Hs)
Ensembl Gene ENSG00000113916 (Hs), ENSMUSG00000022508 (Mm), ENSRNOG00000001843 (Rn)
Entrez Gene 604 (Hs), 12053 (Mm), 303836 (Rn)
Human Protein Atlas ENSG00000113916 (Hs)
KEGG Gene hsa:604 (Hs), mmu:12053 (Mm), rno:303836 (Rn)
OMIM 109565 (Hs)
Pharos P41182 (Hs)
RefSeq Nucleotide NM_001130845 (Hs), NM_001348026 (Mm), NM_001107084 (Rn)
RefSeq Protein NP_001124317 (Hs), NP_001334955 (Mm), NP_001100554 (Rn)
UniProtKB P41182 (Hs), P41183 (Mm)
Wikipedia BCL6 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the BCL6 BTB domain in complex with OICR-12694 (JNJ-65234637)
PDB Id:  7LWG
Ligand:  JNJ-65234637
Resolution:  1.3Å
Species:  Human
References:  7

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
JNJ-65234637 Small molecule or natural product Ligand has a PDB structure Hs Binding 8.3 pKd 7
⤷ pKd 8.3 (Kd 5x10-9 M) [7]
FX1 Small molecule or natural product Primary target of this compound Hs Binding 5.2 pKd 2
⤷ pKd 5.2 (Kd 7x10-6 M) [2]
Description: Binding of compound to BCL6 BTB domain using microscale thermophoresis.
BCL6 PROTAC 15 Small molecule or natural product Hs Inhibition 6.9 pIC50 8
⤷ pIC50 6.9 (IC50 1.2x10-7 M) [8]
compound 8c [PMID: 28760529] Small molecule or natural product Immunopharmacology Ligand Hs Binding 6.1 – 7.0 pIC50 9
⤷ pIC50 7.0 (IC50 1x10-7 M) [9]
Description: In a cell-free ELISA system measuring ability to inhibit BCL6 BTB domain-NCoR interaction.
pIC50 6.1 (IC50 7.2x10-7 M) [9]
Description: In a cell-based mammalian two-hybrid system assessing inhibition of protein-protein interaction between BCL6 BTB domain and BCoR.
Inhibitor Comments
The BCL6 inhibitor 79-6 (PubChem CID 5721353) is commercially available but it is less potent (Kd 138 μM) than the compounds listed in the table above. 79-6 is active in vitro and in vivo, and is reported to be selective for BCL6 over the related transcription factors Kaiso (ZBTB33), HIC1, and PLZF (ZBTB16) [3].
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BI-3802 Small molecule or natural product Ligand has a PDB structure Hs Binding >8.5 pIC50 6
⤷ pIC50 >8.5 (IC50 <3x10-9 M) [6]
Immunopharmacology Comments
BCL6/corepressor complexes are important for the formation of germinal centers and differentiation and proliferation of lymphocytes. Oncogenic mutations in BCL6 lead to the development of diffuse large B-cell lymphoma cells from germinal center B cells. Disruption of BCL6/corepressor complex formation by pharmacological inhibitors has therefore been identified as a novel drug mechanism with potential for the treatment of autoimmune diseases and cancer [2-3].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
General Comments
B-cell lymphoma 6 (BCL6) protein is a transcriptional repressor that is involved in protein-protein interactions with corepressors such as CL6 corepressor (BCoR) [4], silencing mediator for retinoid and thyroid receptors (SMRT) [1], and nuclear receptor corepressor (NCoR) [5]. Most diffuse large cell lymphomas and many follicular lymphomas contain oncogenic and deregulating mutations in BCL6.

References

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1. Ahmad KF, Melnick A, Lax S, Bouchard D, Liu J, Kiang CL, Mayer S, Takahashi S, Licht JD, Privé GG. (2003) Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Mol Cell, 12 (6): 1551-64. [PMID:14690607]

2. Cardenas MG, Yu W, Beguelin W, Teater MR, Geng H, Goldstein RL, Oswald E, Hatzi K, Yang SN, Cohen J et al.. (2016) Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma. J Clin Invest, 126 (9): 3351-62. [PMID:27482887]

3. Cerchietti LC, Ghetu AF, Zhu X, Da Silva GF, Zhong S, Matthews M, Bunting KL, Polo JM, Farès C, Arrowsmith CH et al.. (2010) A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell, 17 (4): 400-11. [PMID:20385364]

4. Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Privé GG. (2008) Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell, 29 (3): 384-91. [PMID:18280243]

5. Huynh KD, Bardwell VJ. (1998) The BCL-6 POZ domain and other POZ domains interact with the co-repressors N-CoR and SMRT. Oncogene, 17 (19): 2473-84. [PMID:9824158]

6. Kerres N, Steurer S, Schlager S, Bader G, Berger H, Caligiuri M, Dank C, Engen JR, Ettmayer P, Fischerauer B et al.. (2017) Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6. Cell Rep, 20 (12): 2860-2875. [PMID:28930682]

7. Mamai A, Chau AM, Wilson BJ, Watson ID, Joseph BB, Subramanian PR, Morshed MM, Morin JA, Prakesch MA, Lu T et al.. (2023) Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor. ACS Med Chem Lett, 14 (2): 199-210. [PMID:36793435]

8. McCoull W, Cheung T, Anderson E, Barton P, Burgess J, Byth K, Cao Q, Castaldi MP, Chen H, Chiarparin E et al.. (2018) Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6. ACS Chem Biol, 13 (11): 3131-3141. [PMID:30335946]

9. Yasui T, Yamamoto T, Sakai N, Asano K, Takai T, Yoshitomi Y, Davis M, Takagi T, Sakamoto K, Sogabe S et al.. (2017) Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design. Bioorg Med Chem, 25 (17): 4876-4886. [PMID:28760529]

How to cite this page

BTB (POZ) domain containing TFs: BCL6 transcription repressor. Last modified on 01/03/2023. Accessed on 11/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2957.