2WMR

Crystal structure of checkpoint kinase 1 (Chk1) in complex with inhibitors

Summary for 2WMR

• Entry DOI: 10.2210/pdb2wmr/pdb
• Related: 1IA8 1NVQ 1NVR 1NVS 1ZLT 1ZYS 2AYP 2BR1 2BRB 2BRG 2BRH 2BRM 2BRN 2BRO 2C3J 2C3K 2C3L 2CGU 2CGV 2CGW 2CGX 2WMQ 2WMS 2WMT 2WMU 2WMV 2WMW 2WMX
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK1, 5,6,7,8-TETRAHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase, polymorphism, phosphoprotein, ubl conjugation, isopeptide bond, checkpoint kinase, nucleotide-binding, serine/threonine kinase, dna damage, dna repair, atp-binding, transferase, chk1, kinase, nucleus, cytoplasm, cell cycle
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 33249.25

Authors

Matthews, T.P.,Klair, S.,Burns, S.,Boxall, K.,Cherry, M.,Fisher, M.,Westwood, I.M.,Walton, M.I.,McHardy, T.,Cheung, K.-M.J.,Van Montfort, R.,Williams, D.,Aherne, G.W.,Garrett, M.D.,Reader, J.,Collins, I. (deposition date: 2009-07-03, release date: 2009-07-28, Last modification date: 2023-12-13)

Primary citation

Matthews, T.P.,Klair, S.,Burns, S.,Boxall, K.,Cherry, M.,Fisher, M.,Westwood, I.M.,Walton, M.I.,Mchardy, T.,Cheung, K.-M.J.,Van Montfort, R.,Williams, D.,Aherne, G.W.,Garrett, M.D.,Reader, J.,Collins, I.
Identification of Inhibitors of Checkpoint Kinase 1 Through Template Screening.
J.Med.Chem., 52:4810-, 2009

PubMed Abstract: Checkpoint kinase 1 (CHK1) is an oncology target of significant current interest. Inhibition of CHK1 abrogates DNA damage-induced cell cycle checkpoints and sensitizes p53 deficient cancer cells to genotoxic therapies. Using template screening, a fragment-based approach to small molecule hit generation, we have identified multiple CHK1 inhibitor scaffolds suitable for further optimization. The sequential combination of in silico low molecular weight template selection, a high concentration biochemical assay and hit validation through protein-ligand X-ray crystallography provided 13 template hits from an initial in silico screening library of ca. 15000 compounds. The use of appropriate counter-screening to rule out nonspecific aggregation by test compounds was essential for optimum performance of the high concentration bioassay. One low molecular weight, weakly active purine template hit was progressed by iterative structure-based design to give submicromolar pyrazolopyridines with good ligand efficiency and appropriate CHK1-mediated cellular activity in HT29 colon cancer cells.

PubMed: 19572549
DOI: 10.1021/JM900314J

Experimental method

X-RAY DIFFRACTION (2.43 Å)