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

ACS Med Chem Lett. 2017 Mar 31;8(5):543-548. doi: 10.1021/acsmedchemlett.7b00091.

Cheng Mo ¹ ², Zhang Zhang ³, Christopher P Guise ⁴ ⁵, Xueqiang Li ¹ ², Jinfeng Luo ¹, Zhengchao Tu ¹, Yong Xu ¹, Adam V Patterson ⁴ ⁵, Jeff B Smaill ⁴ ⁵, Xiaomei Ren ³, Xiaoyun Lu ³, Ke Ding ³

Affiliations

1 State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, # 190 Kaiyuan Avenue, Guangzhou 510530, China.
2 University of Chinese Academy of Sciences, # 19 Yuquan Road, Beijing 100049, China.
3 School of Pharmacy, Jinan University, # 601 Huangpu Avenue West, Guangzhou 510632, China.
4 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, #92019 Private Bag, Auckland 1142, New Zealand.
5 Auckland Cancer Society Research Centre, University of Auckland, #92019 Private Bag, Auckland 1142, New Zealand.

PMID: 28523108 DOI: 10.1021/acsmedchemlett.7b00091

Abstract

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 IC₅₀ value of 0.38 μM. 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 μM, respectively.

Keywords

Selective FGFR4 inhibitor; breast cancer; hepatocellular carcinoma; targeted therapy.

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