Discovery and Characterization of 2-Anilino-4-(Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents

被引：93

作者：

Wang, Shudong ^{[1
]}

Griffiths, Gary ^{[1
]}

Midgley, Carol A. ^{[1
]}

Barnett, Anna L. ^{[1
]}

Cooper, Michael ^{[1
]}

Grabarek, Joanna ^{[1
]}

Ingram, Laura ^{[1
]}

Jackson, Wayne ^{[1
]}

Kontopidis, George ^{[1
]}

McClue, Steven J. ^{[1
]}

McInnes, Campbell ^{[1
]}

McLachlan, Janice ^{[1
]}

Meades, Christopher ^{[1
]}

Mezna, Mokdad ^{[1
]}

Stuart, Iain ^{[1
]}

Thomas, Mark P. ^{[1
]}

Zheleva, Daniella I. ^{[1
]}

Lane, David P. ^{[1
]}

Jackson, Robert C. ^{[1
]}

Glover, David M. ^{[1
]}

Blake, David G. ^{[1
]}

Fischer, Peter M. ^{[1
]}

机构：

[1] Cyclacel Ltd, Dundee DD1 5JJ, Scotland

来源：

CHEMISTRY & BIOLOGY | 2010年 / 17卷 / 10期

关键词：

RNA-POLYMERASE-II; DEPENDENT KINASE INHIBITOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; CARBOXYL-TERMINAL DOMAIN; P-TEFB; BIOLOGICAL-ACTIVITY; APOPTOSIS PROTEINS; P53; FLAVOPIRIDOL; CELLS;

D O I：

10.1016/j.chembiol.2010.07.016

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：

The main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i e, CDK7 and especially CDK9 The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups We describe the charaterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H-thiazol-2-one, with anticancer activity in animal models

引用

页码：1111 / 1121

页数：11

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[1] Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria [J].