2WTD

Crystal structure of Chk2 in complex with an inhibitor

Summary for 2WTD

• Entry DOI: 10.2210/pdb2wtd/pdb
• Related: 1GXC 2CN5 2CN8 2W0J 2W7X 2WTC 2WTI 2WTJ
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK2, 4-[2-AMINO-5-(1,3-BENZODIOXOL-4-YL)PYRIDIN-3-YL]BENZAMIDE, NITRATE ION, ... (5 entities in total)
• Functional Keywords: transferase, kinase, cell cycle, li-fraumeni syndrome
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform 2: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 9: Nucleus. Isoform 12: Nucleus. Nucleus, PML body: O96017
• Total number of polymer chains: 1
• Total formula weight: 37693.39

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: 2009-09-15, 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 (2.75 Å)