6tom | pdb_00006tom

Crystal structure of human BCL6 BTB domain in complex with compound 1

spinqualitylabelsall models 6tom, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tom is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, NQZ Gene: BCL6, BCL5, LAZ3, ZBTB27, ZNF51 (HUMAN) 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. Publication Abstract from PubMed Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing. Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.,Bellenie BR, Cheung KJ, Varela A, Pierrat OA, Collie GW, Box GM, Bright MD, Gowan S, Hayes A, Rodrigues MJ, Shetty KN, Carter M, Davis OA, Henley AT, Innocenti P, Johnson LD, Liu M, de Klerk S, Le Bihan YV, Lloyd MG, McAndrew PC, Shehu E, Talbot R, Woodward HL, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Hoelder S J Med Chem. 2020 Apr 10. doi: 10.1021/acs.jmedchem.9b02076. PMID:32275432 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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