Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: Development of chemical probe ML315

被引：45

作者：

Coombs, Thomas C. ^{[1
]}

Tanega, Cordelle ^{[2
]}

Shen, Min ^{[2
]}

Wang, Jenna L. ^{[1
]}

Auld, Douglas S. ^{[2
]}

Gerritz, Samuel W. ^{[3
]}

Schoenen, Frank J. ^{[1
]}

Thomas, Craig J. ^{[2
]}

Aube, Jeffrey ^{[1
,4
]}

机构：

[1] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66047 USA

[2] NIH, NIH Chem Genom Ctr, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA

[3] Bristol Myers Squibb Res, Wallingford, CT 06492 USA

[4] Univ Kansas, Dept Med Chem, Lawrence, KS 66047 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 12期

基金：

美国国家卫生研究院;

关键词：

Clk; Dyrk; Kinase inhibitor; Splicing; Pyrimidine; NEURONAL DIFFERENTIATION; SUBSTRATE-SPECIFICITY; DOWN-SYNDROME; FAMILY; OVEREXPRESSION; COMBINATION; ACTIVATION; EXPRESSION; DISEASE;

D O I：

10.1016/j.bmcl.2013.02.096

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：3654 / 3661

页数：8

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