DNA-dependent protein kinase (DNA-PK) inhibitors: Structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

被引：20

作者：

Clapham, Kate M. ^{[1
]}

Bardos, Julia ^{[2
]}

Finlay, M. Raymond V. ^{[3
]}

Golding, Bernard T. ^{[1
]}

Griffen, Edward J. ^{[3
]}

Griffin, Roger J. ^{[1
]}

Hardcastle, Ian R. ^{[1
]}

Menear, Keith A. ^{[2
]}

Ting, Attilla ^{[3
]}

Turner, Paul ^{[3
]}

Young, Gail L. ^{[3
]}

Cano, Celine ^{[1
]}

机构：

[1] Newcastle Univ, Newcastle Canc Ctr, No Inst Canc Res, Sch Chem, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[2] KuDOS Pharmaceut Ltd, Cambridge CB4 0PE, England

[3] AstraZeneca Oncol IMed, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 03期

关键词：

DNA repair; DNA-PK; Kinase inhibitors; Anticancer drugs; Structure-activity relationship studies; HUMAN TUMOR-CELLS; STRAND BREAK; POTENT; WORTMANNIN; RADIOSENSITIZATION; IDENTIFICATION; RADIATION; LY294002; NU7441; DAMAGE;

D O I：

10.1016/j.bmcl.2010.12.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110 alpha), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC50 = 8 nM). (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：966 / 970

页数：5

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