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

被引：76

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

共 73 条

[1]

Adams J.L., 2007, Patent No. [WO 2007024843 A2 20070301, 2007024843, WO 2007024843]

[2] Design and synthesis of pyridazinone-based 5-HT2C agonists [J].

Allerton, Charlotte M. N. ;

Andrews, Mark D. ;

Blagg, Julian ;

Ellis, David ;

Evrard, Edel ;

Green, Martin P. ;

Liu, Kevin K. -C. ;

McMurray, Gordon ;

Ralph, Michael ;

Sanderson, Vivienne ;

Ward, Robin ;

Watson, Lesa .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (19) :5791-5795

[3]

Amin HM, 2003, ARCH PATHOL LAB MED, V127, P424

[4] Imidazoles: SAR and development of a potent class of cyclin-dependent kinase inhibitors [J].

Anderson, Malcolm ;

Andrews, David M. ;

Barker, Andy J. ;

Brassington, Claire A. ;

Breed, Jason ;

Byth, Kate F. ;

Culshaw, Janet D. ;

Finlay, M. Raymond V. ;

Fisher, Eric ;

McMiken, Helen H. J. ;

Green, Clive P. ;

Heaton, Dave W. ;

Nash, Ian A. ;

Newcombe, Nicholas J. ;

Oakes, Sandra E. ;

Pauptit, Richard A. ;

Roberts, Andrew ;

Stanway, Judith J. ;

Thomas, Andrew P. ;

Tucker, Julie A. ;

Walker, Mike ;

Weir, Hazel M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (20) :5487-5492

[5] Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1 [J].

Aubry, Carine ;

Wilson, A. James ;

Emmerson, Daniel ;

Murphy, Emma ;

Chan, Yu Yam ;

Dickens, Michael P. ;

Garcia, Marcos D. ;

Jenkins, Paul R. ;

Mahale, Sachin ;

Chaudhuri, Bhabatosh .

BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (16) :6073-6084

[6] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[7]

BENNETT MJ, 2007, Patent No. 2007105058

[8] Clinical anticancer drug development: targeting the cyclin-dependent kinases [J].

Benson, C ;

Kaye, S ;

Workman, P ;

Garrett, M ;

Walton, M ;

de Bono, J .

BRITISH JOURNAL OF CANCER, 2005, 92 (01) :7-12

[9] Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma [J].

Bergsagel, PL ;

Kuehl, WM ;

Zhan, FH ;

Sawyer, J ;

Barlogie, B ;

Shaughnessy, J .

BLOOD, 2005, 106 (01) :296-303

[10] Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma [J].

Bergsagel, PL ;

Kuehl, WM .

IMMUNOLOGICAL REVIEWS, 2003, 194 (01) :96-104

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