Design of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to Interrogate the Relationship of EGFR and GAK in Chordoma

被引：30

作者：

Asquith, Christopher R. M. ^{[1
,2
]}

Naegeli, Kaleb M. ^{[3
]}

East, Michael P. ^{[2
]}

Laitinen, Tuomo ^{[4
]}

Havener, Tammy M. ^{[3
]}

Wells, Carrow I. ^{[1
]}

Johnson, Gary L. ^{[2
]}

Drewry, David H. ^{[1
]}

Zuercher, William J. ^{[1
,5
]}

Morris, David C. ^{[3
]}

机构：

[1] Univ N Carolina, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, UNC Catalyst Rare Dis, Chapel Hill, NC 27599 USA

[4] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland

[5] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 09期

基金：

巴西圣保罗研究基金会; 加拿大创新基金会;

关键词：

4-ANILINOQUINOLINES; EXPRESSION; MUTATIONS;

D O I：

10.1021/acs.jmedchem.9b00350

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.

引用

页码：4772 / 4778

页数：7

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