PDBsum entry 5n1v

Transferase

PDB id: 5n1v

Contents

Protein chains

331 a.a.

Ligands

SO4 ×7

EDO ×16

8GQ ×2

Waters ×141

PDB id:

5n1v

Name:

Transferase

Title:

Crystal structure of the protein kinase ck2 catalytic subunit in complex with pyrazolo-pyrimidine macrocyclic ligand

Structure:

Casein kinase ii subunit alpha. Chain: a, b. Synonym: ck ii alpha. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csnk2a1, ck2a1. Expressed in: komagataella pastoris. Expression_system_taxid: 4922

Resolution:

2.52Å R-factor: 0.189 R-free: 0.229

Authors:

G.Robb,A.Ferguson,D.Hargreaves

Key ref:

W.McCoull et al. (2017). 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. PubMed id: 28485934 DOI: 10.1021/acs.jmedchem.7b00359

Date:

06-Feb-17 Release date: 17-May-17

Protein chains

P68400  (CSK21_HUMAN) -  Casein kinase II subunit alpha from Homo sapiens

Seq: 391 a.a.

Struc: 331 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.7b00359

J Med Chem 60:4386-4402 (2017)

PubMed id: 28485934

Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors.

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

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.