Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets

被引：11

作者：

Lai, JYQ ^{[1
]}

Langston, S ^{[1
]}

Adams, R ^{[1
]}

Beevers, RE ^{[1
]}

Boyce, R ^{[1
]}

Burckhardt, S ^{[1
]}

Cobb, J ^{[1
]}

Ferguson, Y ^{[1
]}

Figueroa, E ^{[1
]}

Grimster, N ^{[1
]}

Henry, AH ^{[1
]}

Khan, N ^{[1
]}

Jenkins, K ^{[1
]}

Jones, MW ^{[1
]}

Judkins, R ^{[1
]}

Major, J ^{[1
]}

Masood, A ^{[1
]}

Nally, J ^{[1
]}

Payne, H ^{[1
]}

Payne, L ^{[1
]}

Raphy, G ^{[1
]}

Raynham, T ^{[1
]}

Reader, J ^{[1
]}

Reader, Y ^{[1
]}

Reid, A ^{[1
]}

Ruprah, P ^{[1
]}

Shaw, M ^{[1
]}

Sore, H ^{[1
]}

Stirling, M ^{[1
]}

Talbot, A ^{[1
]}

Taylor, J ^{[1
]}

Thompson, S ^{[1
]}

Wada, H ^{[1
]}

Walker, D ^{[1
]}

机构：

[1] Millennium Pharmaceut R&D Ltd, Cambridge CB1 6ET, England

来源：

MEDICINAL RESEARCH REVIEWS | 2005年 / 25卷 / 03期

关键词：

lead generation; kinase inhibitors; parallel synthesis; high-throughput screening;

D O I：

10.1002/med.20026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare > 500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection. (c) 2004 Wiley Periodicals, Inc.

引用

页码：310 / 330

页数：21

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