Discovery and SAR of 5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic Acid (CX-4945), the First Clinical Stage Inhibitor of Protein Kinase CK2 for the Treatment of Cancer

被引：261

作者：

Pierre, Fabrice ^{[1
]}

Chua, Peter C. ^{[1
]}

O'Brien, Sean E. ^{[1
]}

Siddiqui-Jain, Adam ^{[1
]}

Bourbon, Pauline ^{[1
]}

Haddach, Mustapha ^{[1
]}

Michaux, Jerome ^{[1
]}

Nagasawa, Johnny ^{[1
]}

Schwaebe, Michael K. ^{[1
]}

Stefan, Eric ^{[1
]}

Vialettes, Anne ^{[1
]}

Whitten, Jeffrey P. ^{[1
]}

Chen, Ta Kung ^{[1
]}

Darjania, Levan ^{[1
]}

Stansfield, Ryan ^{[1
]}

Anderes, Kenna ^{[1
]}

Bliesath, Josh ^{[1
]}

Drygin, Denis ^{[1
]}

Ho, Caroline ^{[1
]}

Omori, May ^{[1
]}

Proffitt, Chris ^{[1
]}

Streiner, Nicole ^{[1
]}

Trent, Katy ^{[1
]}

Rice, William G. ^{[1
]}

Ryckman, David M. ^{[1
]}

机构：

[1] Cylene Pharmaceut, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 02期

关键词：

SQUAMOUS-CELL CARCINOMA; STRUCTURE-BASED DESIGN; POTENT INHIBITORS; DERIVATIVES; CK2-ALPHA; SELECTIVITY; POLYMERASE; APOPTOSIS; SUBUNIT; TARGET;

D O I：

10.1021/jm101251q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2's small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (K-i = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.

引用

页码：635 / 654

页数：20

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