View source for 9q03


==Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BCL6-760 (LDD, local refined)==
<StructureSection load='9q03' size='340' side='right'caption='[[9q03]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9q03]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9Q03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Q03 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.15&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CM7:(3R)-3-(6-{4-[(5-chloro-4-{[3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl]amino}pyrimidin-2-yl)(methyl)amino]piperidin-1-yl}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione'>A1CM7</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9q03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9q03 OCA], [https://pdbe.org/9q03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9q03 RCSB], [https://www.ebi.ac.uk/pdbsum/9q03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9q03 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/BCL6_HUMAN 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 ==
[https://www.uniprot.org/uniprot/BCL6_HUMAN BCL6_HUMAN] Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.<ref>PMID:9649500</ref> <ref>PMID:18280243</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The discovery of a potent and selective BCL6 ligand-directed degrader (LDD), BCL6-760 (45) is described. Through structure-activity relationships, the most potent heterobifunctional degraders of BCL6 were found to be those containing short aminopiperidine linkers in combination with an indazole-based cereblon (CRBN)-binding moiety (CBM). In vitro ADME profiling of potent molecules identified BCL6-760 as an ideal molecule for use in in vivo experiments due to its good passive permeability, solubility, and microsomal stability. Mechanistic studies confirmed that BCL6 degradation is CRBN mediated, and proteomic assessment indicates a clean and selective degradation profile. BCL6-760 exhibited good oral mouse PK and was capable of penetrant and sustained PD effects. At 60 mg/kg BID dosing, BCL6-760 achieves &gt;90% BCL6 reduction and leads to an overall 64% tumor volume reduction in an OCI-LY-1 mouse xenograft efficacy model.

Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760.,Shunatona HP, Holmberg Douglas N, Rhodes J, Thomas W, Da Silva D, Gamez J, Groza M, Christoforou A, Zhu J, Johnson S, Dodd D, Huang D, Griffin J, Miseo G, Whitefield B, Weiss D, Rader J, Kuzu E, Leisten J, Del Rosario J, Shi L, Matyskiela M, Chamberlain PP, Belmont P, Alexander M, Zapf CW, Groocock L, Mortensen DS J Med Chem. 2025 Oct 7. doi: 10.1021/acs.jmedchem.5c01645. PMID:41055242<ref>PMID:41055242</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9q03" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fang W]]
[[Category: Pagarigan B]]
[[Category: Zhu J]]