2-Oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors

  • Eur J Med Chem. 2017 Jul 28:135:531-543. doi: 10.1016/j.ejmech.2017.04.049.
Xueqiang Li  1 ,  Christopher P Guise  2 ,  Rana Taghipouran  3 ,  Yuliana Yosaatmadja  4 ,  Amir Ashoorzadeh  3 ,  Woo-Kyong Paik  4 ,  Christopher J Squire  5 ,  Shuang Jiang  1 ,  Jinfeng Luo  6 ,  Yong Xu  6 ,  Zheng-Chao Tu  6 ,  Xiaoyun Lu  7 ,  Xiaomei Ren  7 ,  Adam V Patterson  8 ,  Jeff B Smaill  9 ,  Ke Ding  10
Affiliations
  • 1. Guangzhou Institutes of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Chinese Academy of Sciences, No.190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 2. Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 3. Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 4. School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 5. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 6. Guangzhou Institutes of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Chinese Academy of Sciences, No.190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 7. School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 8. Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: [email protected].
  • 9. Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: [email protected].
  • 10. Guangzhou Institutes of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Chinese Academy of Sciences, No.190 Kaiyuan Avenue, Guangzhou 510530, China; School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: [email protected].
PMID: 28521156 DOI: 10.1016/j.ejmech.2017.04.049
Abstract

A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC50 values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung Cancer cells, FGFR2-amplified SUM52 breast Cancer cells and FGFR3-amplified SW780 bladder Cancer cells with low nanomolar IC50 values, but was significantly less potent against four FGFR-negative Cancer cell lines, with low micromolar IC50 values. Biological investigation also confirmed the irreversible binding of the molecule with the FGFR1-3 target kinases. Compound 2l may serve as a promising new lead for further Anticancer drug discovery.

Keywords
2-Oxo-3,4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives; FGFR; Irreversible inhibitor.