5n21

From Proteopedia

Crystal structure of the BCL6 BTB domain in complex with pyrazolo-pyrimidine ligand

PDB ID 5n21

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Structural highlights

5n21 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.58Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BCL6_HUMAN Note=Chromosomal aberrations involving BCL6 may be a cause of B-cell non-Hodgkin lymphoma. Translocation t(3;14)(q27;q32); translocation t(3;22)(q27;q11) with immunoglobulin gene regions. Note=A chromosomal aberration involving BCL6 may be a cause of a form of B-cell leukemia. Translocation t(3;11)(q27;q23) with POU2AF1/OBF1. Note=A chromosomal aberration involving BCL6 may be a cause of lymphoma. Translocation t(3;4)(q27;p11) with ARHH/TTF.

Function

BCL6_HUMAN Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.^[1] ^[2]

Publication Abstract from PubMed

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors.,McCoull W, Abrams RD, Anderson E, Blades K, Barton P, Box M, Burgess J, Byth K, Cao Q, Chuaqui C, Carbajo RJ, Cheung T, Code E, Ferguson AD, Fillery S, Fuller NO, Gangl E, Gao N, Grist M, Hargreaves D, Howard MR, Hu J, Kemmitt PD, Nelson JE, O'Connell N, Prince DB, Raubo P, Rawlins PB, Robb GR, Shi J, Waring MJ, Whittaker D, Wylot M, Zhu X J Med Chem. 2017 May 9. doi: 10.1021/acs.jmedchem.7b00359. PMID:28485934^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Niu H, Ye BH, Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 1998 Jul 1;12(13):1953-61. PMID:9649500
↑ Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Prive GG. Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell. 2008 Feb 15;29(3):384-91. PMID:18280243 doi:10.1016/j.molcel.2007.12.026
↑ McCoull W, Abrams RD, Anderson E, Blades K, Barton P, Box M, Burgess J, Byth K, Cao Q, Chuaqui C, Carbajo RJ, Cheung T, Code E, Ferguson AD, Fillery S, Fuller NO, Gangl E, Gao N, Grist M, Hargreaves D, Howard MR, Hu J, Kemmitt PD, Nelson JE, O'Connell N, Prince DB, Raubo P, Rawlins PB, Robb GR, Shi J, Waring MJ, Whittaker D, Wylot M, Zhu X. Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors. J Med Chem. 2017 May 9. doi: 10.1021/acs.jmedchem.7b00359. PMID:28485934 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00359