2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors

被引：37

作者：

Mo, Cheng ^{[1
,2
]}

Zhang, Zhang ^{[3
]}

Guise, Christopher P. ^{[4
,5
]}

Li, Xueqiang ^{[1
,2
]}

Luo, Jinfeng ^{[1
]}

Tu, Zhengchao ^{[1
]}

Xu, Yong ^{[1
]}

Patterson, Adam V. ^{[4
,5
]}

Smaill, Jeff B. ^{[4
,5
]}

Ren, Xiaomei ^{[3
]}

Lu, Xiaoyun ^{[3
]}

Ding, Ke ^{[3
]}

机构：

[1] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, 190 Kaiyuan Ave, Guangzhou 510530, Guangdong, Peoples R China

[2] Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China

[3] Jinan Univ, Sch Pharm, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China

[4] Univ Auckland, Aucldand Canc Soc, Res Ctr, 92019 Private Bag, Auckland 1142, New Zealand

[5] Univ Auckland, Maurice Wilkins Ctr Mol Biodiscovery, 92019 Private Bag, Auckland 1142, New Zealand

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 05期

基金：

中国国家自然科学基金;

关键词：

Selective FGFR4 inhibitor; targeted therapy; breast cancer; hepatocellular carcinoma; ADVANCED SOLID TUMORS; HEPATOCELLULAR-CARCINOMA; DOSE-ESCALATION; BREAST-CANCER; KLOTHO-BETA; PHASE-I; TARGET; FGF19; PROLIFERATION; HOMEOSTASIS;

D O I：

10.1021/acsmedchemlett.7b00091

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 2-aminopyrimidine derivatives were designed and synthesized as highly selective FGFR4 inhibitors. One of the most promising compounds 2n tightly bound FGFR4 with a K-d value of 3.3 nM and potently inhibited its enzymatic activity with an IC50 value of 2.6 nM, but completely spared FGFR1/2/3. The compound selectively suppressed proliferation of breast cancer cells harboring dysregulated FGFR4 signaling with an 1050 value of 0.38 mu M. Furthermore, 2n exhibited extraordinary target specificity in a Kinome-wide screen against 468 kinases, with S(35) and S(10) selectivity scores of 0.01 and 0.007 at 1.0 mu M, respectively.

引用

页码：543 / 548

页数：6

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