7okj

Crystal structure of human BCL6 BTB domain in complex with compound 12c and its enantiomer 12b

spinqualitylabelsall models 7okj, resolution 1.43Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7okj is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.43Å Ligands: CL, EDO, VHN, VHZ 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 We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets. Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.,Lloyd MG, Huckvale R, Cheung KJ, Rodrigues MJ, Collie GW, Pierrat OA, Gatti Iou M, Carter M, Davis OA, McAndrew PC, Gunnell E, Le Bihan YV, Talbot R, Henley AT, Johnson LD, Hayes A, Bright MD, Raynaud FI, Meniconi M, Burke R, van Montfort RLM, Rossanese OW, Bellenie BR, Hoelder S J Med Chem. 2021 Nov 30. doi: 10.1021/acs.jmedchem.1c00946. PMID:34846884 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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