Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B

被引：42

作者：

Collins, I

Caldwell, J

Fonseca, T

Donald, A

Bavetsias, V

Hunter, LJK

Garrett, MD

Rowlands, MG

Aherne, GW

Davies, TG

Berdini, V

Woodhead, SJ

Davis, D

Seavers, LCA

Wyatt, PG

Workman, P

McDonald, E

机构：

[1] Inst Canc Res, UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England

[2] Astex Technol Ltd, Cambridge CB4 0QA, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2006年 / 14卷 / 04期

关键词：

PKB; inhibitors; cancer; structure-based drug design;

D O I：

10.1016/j.bmc.2005.09.055

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Structure-based drug design of novel isoquinoline-5-sulfonamide inhibitors of PKB as potential antitumour agents was investigated. Constrained pyrrolidine analogues that mimicked the bound conformation of linear prototypes were identified and investigated by co-crystal structure determinations with the related protein PKA. Detailed variation in the binding modes between inhibitors with similar overall conformations was observed. Potent PKB inhibitors from this series inhibited GSK3 beta phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells. (c) 2005 Elsevier Ltd. All rights reserved.

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页码：1255 / 1273

页数：19

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