5N1V

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

Summary for 5N1V

• Entry DOI: 10.2210/pdb5n1v/pdb
• Descriptor: Casein kinase II subunit alpha, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P68400
• Total number of polymer chains: 2
• Total formula weight: 84605.93

Authors

Robb, G.,Ferguson, A.,Hargreaves, D. (deposition date: 2017-02-06, release date: 2017-05-17, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.52 Å)