9q03

Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BCL6-760 (LDD, local refined)

spinqualitylabelsall models 9q03, resolution 3.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9q03 is a 3 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: Electron Microscopy, Resolution 3.15Å Ligands: A1CM7, ZN 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 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 >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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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