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 Kd 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.