2WTI

CRYSTAL STRUCTURE OF CHK2 IN COMPLEX WITH AN INHIBITOR

2WTI の概要

• エントリーDOI: 10.2210/pdb2wti/pdb
• 関連するPDBエントリー: 2WTC 2WTD 2WTJ
• 分子名称: CHECKPOINT KINASE 2, 4-[2-AMINO-5-(2,3-DIHYDROTHIENO[3,4-B][1,4]DIOXIN-5-YL)PYRIDIN-3-YL]BENZAMIDE, NITRATE ION, ... (5 entities in total)
• 機能のキーワード: transferase, kinase, cell cycle, li-fraumeni syndrome
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37713.38

構造登録者

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. (登録日: 2009-09-16, 公開日: 2009-12-29, 最終更新日: 2023-12-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5 Å)