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

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

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: a.patterson@auckland.ac.nz.
  • 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: j.smaill@auckland.ac.nz.
  • 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: dingke@jnu.edu.cn.
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.

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