Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors

被引：38

作者：

Cho, Young Shin ^{[1
]}

Angove, Hayley ^{[2
]}

Brain, Christopher ^{[1
]}

Chen, Christine Hiu-Tung ^{[1
]}

Cheng, Hong ^{[1
]}

Cheng, Robert ^{[2
]}

Chopra, Rajiv ^{[1
]}

Chung, Kristy ^{[1
]}

Congreve, Miles ^{[2
]}

Dagostin, Claudio ^{[2
]}

Davis, Deborah J. ^{[2
]}

Felten, Ruth ^{[2
]}

Giraldes, John ^{[1
]}

Hiscock, Steven D. ^{[2
]}

Kim, Sunkyu ^{[1
]}

Kovats, Steven ^{[1
]}

Lagu, Bharat ^{[1
]}

Lewry, Kim ^{[2
]}

Loo, Alice ^{[1
]}

Lu, Yipin ^{[1
]}

Luzzio, Michael ^{[1
]}

Maniara, Wiesia ^{[1
]}

McMenamin, Rachel ^{[2
]}

Mortenson, Paul N. ^{[2
]}

Benning, Rajdeep ^{[2
]}

O'Reilly, Marc ^{[2
]}

Rees, David C. ^{[2
]}

Shen, Junqing ^{[1
]}

Smith, Troy ^{[1
]}

Wang, Yaping ^{[1
]}

Williams, Glyn ^{[2
]}

Woolford, Alison J. -A. ^{[2
]}

Wrona, Wojciech ^{[1
]}

Xu, Mei ^{[1
]}

Yang, Fan ^{[1
]}

Howard, Steven ^{[2
]}

机构：

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

[2] Astex Pharmaceut Inc, Cambridge CB4 0QA, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 06期

关键词：

CDK4/6; pRb phosphorylation; mantle cell lymphoma; fragment-based screening; structure-guided optimization; MANTLE CELL LYMPHOMA; RETINOBLASTOMA PROTEIN; GENETIC ALGORITHM; CANCER; CYCLE; INACTIVATION;

D O I：

10.1021/ml200241a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

引用

页码：445 / 449

页数：5

共 26 条

[1] Amin HM, 2003, ARCH PATHOL LAB MED, V127, P424
[2] 4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6
Cho, Young Shin
Borland, Maria
Brain, Christopher
Chen, Christine H. -T
Cheng, Hong
Chopra, Rajiv
Chung, Kristy
Groarke, James
He, Guo
Hou, Ying
Kim, Sunkyu
Kovats, Steven
Lu, Yipin
O'Reilly, Marc
Shen, Junqing
Smith, Troy
Trakshel, Gary
Voegtle, Markus
Xu, Mei
Xu, Ming
Sung, Moo Je
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (22) : 7938 - 7957
[3] Crystal structure of human CDK4 in complex with a D-type cyclin
Day, Philip J.
Cleasby, Anne
Tickle, Ian J.
O'Reilly, Marc
Coyle, Joe E.
Holding, Finn P.
McMenamin, Rachel L.
Yon, Jeff
Chopra, Rajiv
Lengauer, Christoph
Jhoti, Harren
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (11) : 4166 - 4170
[4] Fry DW, 2004, MOL CANCER THER, V3, P1427
[5] Recent advances in the development of selective small molecule inhibitors for cyclin-dependent kinases
Hirai, H
Kawanishi, N
Iwasawa, Y
[J]. CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (02) : 167 - 179
[6] A novel approach for the development of selective Cdk4 inhibitors: Library design based on locations of Cdk4 specific amino acid residues
Honma, T
Yoshizumi, T
Hashimoto, N
Hayashi, K
Kawanishi, N
Fukasawa, K
Takaki, T
Ikeura, C
Ikuta, M
Suzuki-Takahashi, I
Hayama, T
Nishimura, S
Morishima, H
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (26) : 4628 - 4640
[7] Ligand efficiency: a useful metric for lead selection
Hopkins, AL
Groom, CR
Alex, A
[J]. DRUG DISCOVERY TODAY, 2004, 9 (10) : 430 - 431
[8] MOLECULAR RECOGNITION OF RECEPTOR-SITES USING A GENETIC ALGORITHM WITH A DESCRIPTION OF DESOLVATION
JONES, G
WILLETT, P
GLEN, RC
[J]. JOURNAL OF MOLECULAR BIOLOGY, 1995, 245 (01) : 43 - 53
[9] Development and validation of a genetic algorithm for flexible docking
Jones, G
Willett, P
Glen, RC
Leach, AR
Taylor, R
[J]. JOURNAL OF MOLECULAR BIOLOGY, 1997, 267 (03) : 727 - 748
[10] A CELL-CYCLE REGULATOR POTENTIALLY INVOLVED IN GENESIS OF MANY TUMOR TYPES
KAMB, A
GRUIS, NA
WEAVERFELDHAUS, J
LIU, QY
HARSHMAN, K
TAVTIGIAN, SV
STOCKERT, E
DAY, RS
JOHNSON, BE
SKOLNICK, MH
[J]. SCIENCE, 1994, 264 (5157) : 436 - 440

← 1 2 3 →