5N1V

Crystal structure of the protein kinase CK2 catalytic subunit in complex with pyrazolo-pyrimidine macrocyclic ligand

5N1V の概要

• エントリーDOI: 10.2210/pdb5n1v/pdb
• 分子名称: Casein kinase II subunit alpha, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P68400
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84605.93

構造登録者

Robb, G.,Ferguson, A.,Hargreaves, D. (登録日: 2017-02-06, 公開日: 2017-05-17, 最終更新日: 2024-05-08)

主引用文献

McCoull, W.,Abrams, R.D.,Anderson, E.,Blades, K.,Barton, P.,Box, M.,Burgess, J.,Byth, K.,Cao, Q.,Chuaqui, C.,Carbajo, R.J.,Cheung, T.,Code, E.,Ferguson, A.D.,Fillery, S.,Fuller, N.O.,Gangl, E.,Gao, N.,Grist, M.,Hargreaves, D.,Howard, M.R.,Hu, J.,Kemmitt, P.D.,Nelson, J.E.,O'Connell, N.,Prince, D.B.,Raubo, P.,Rawlins, P.B.,Robb, G.R.,Shi, J.,Waring, M.J.,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., 60:4386-4402, 2017

PubMed Abstract: 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.

PubMed: 28485934
DOI: 10.1021/acs.jmedchem.7b00359

実験手法

X-RAY DIFFRACTION (2.52 Å)