4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

被引：75

作者：

Cho, Young Shin ^{[1
]}

Borland, Maria ^{[1
]}

Brain, Christopher ^{[1
]}

Chen, Christine H. -T ^{[1
]}

Cheng, Hong ^{[1
]}

Chopra, Rajiv ^{[1
]}

Chung, Kristy ^{[1
]}

Groarke, James ^{[1
]}

He, Guo ^{[1
]}

Hou, Ying ^{[1
]}

Kim, Sunkyu ^{[1
]}

Kovats, Steven ^{[1
]}

Lu, Yipin ^{[1
]}

O'Reilly, Marc ^{[2
]}

Shen, Junqing ^{[1
]}

Smith, Troy ^{[1
]}

Trakshel, Gary ^{[1
]}

Voegtle, Markus ^{[1
]}

Xu, Mei ^{[1
]}

Xu, Ming ^{[1
]}

Sung, Moo Je ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Astex Therapeut, Cambridge CB4 0QA, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 22期

关键词：

CRYSTAL-STRUCTURE; D DYSREGULATION; CELL-CYCLE; PROTEIN; POTENT; CDK4; DESIGN; CANCER; AMPLIFICATION; EXPRESSION;

D O I：

10.1021/jm100571n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK 4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK 6. Significant selectivity for CDK4/6 over CDK 1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.

引用

页码：7938 / 7957

页数：20

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