2WTJ

CRYSTAL STRUCTURE OF CHK2 IN COMPLEX WITH AN INHIBITOR

Summary for 2WTJ

• Entry DOI: 10.2210/pdb2wtj/pdb
• Related: 2WTC 2WTD 2WTI
• Descriptor: CHECKPOINT KINASE 2, 2-AMINO-5-(2,3-DIHYDROTHIENO[3,4-B][1,4]DIOXIN-5-YL)-N-[2-(DIMETHYLAMINO)ETHYL]PYRIDINE-3-CARBOXAMIDE, NITRATE ION, ... (5 entities in total)
• Functional Keywords: transferase, kinase, cell cycle, li-fraumeni syndrome
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 37832.55

Authors

Hilton, S.,Naud, S.,Caldwell, J.J.,Boxall, K.,Burns, S.,Anderson, V.E.,Antoni, L.,Allen, C.E.,Pearl, L.H.,Oliver, A.W.,Aherne, G.W.,Garrett, M.D.,Collins, I. (deposition date: 2009-09-16, release date: 2009-12-29, Last modification date: 2023-12-20)

Primary citation

Hilton, S.,Naud, S.,Caldwell, J.J.,Boxall, K.,Burns, S.,Anderson, V.E.,Antoni, L.,Allen, C.E.,Pearl, L.H.,Oliver, A.W.,Aherne, G.W.,Garrett, M.D.,Collins, I.
Identification and Characterisation of 2-Aminopyridine Inhibitors of Checkpoint Kinase 2
Bioorg.Med.Chem., 18:707-, 2010

PubMed Abstract: 5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure-activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic omega-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.

PubMed: 20022510
DOI: 10.1016/J.BMC.2009.11.058

Experimental method

X-RAY DIFFRACTION (2.1 Å)