Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2

被引：74

作者：

Sayle, KL

Bentley, J

Boyle, FT

Calvert, AH

Cheng, YZ

Curtin, NJ

Endicott, JA

Golding, BT

Hardcastle, IR

Jewsbury, P

Mesguiche, V

Newell, DR

Noble, MEM

Parsons, RJ

Pratt, DJ

Wang, LZ

Griffin, RJ

机构：

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

[2] Sch Med, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[3] AstraZeneca Pharmaceut, Macclesfield SK10 4TG, Cheshire, England

[4] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England

[5] Univ Oxford, Mol Biophys Lab, Oxford OX1 3QU, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 18期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

D O I：

10.1016/S0960-894X(03)00651-6

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of O-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidines bearing 2-arylamino substituents was synthesised and evaluated for CDK1 and CDK2 inhibitory activity. Consistent with analogous studies with O-6-Cyclohexylmethylpurines, 2-arylaminopyrimidines with a sulfonamide or carboxamide group at the 4'-position were potent inhibitors, with IC50 values against CDK2 of 1.1 +/- 0.3 and 34 +/- 8 nM, respectively. The crystal structure of the 4'-carboxamide derivative, in complex with phospho-Thr160 CDK2/cyclin A, confirmed the expected binding mode of the inhibitor, and revealed an additional interaction between the carboxamide function and an aspartate residue. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：3079 / 3082

页数：4

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