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

Xueqiang Li; Christopher P Guise; Rana Taghipouran; Yuliana Yosaatmadja; Amir Ashoorzadeh; Woo-Kyong Paik; Christopher J Squire; Shuang Jiang; Jinfeng Luo; Yong Xu; Zheng-Chao Tu; Xiaoyun Lu; Xiaomei Ren; Adam V Patterson; Jeff B Smaill; Ke Ding

doi:10.1016/j.ejmech.2017.04.049

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. Epub 2017 Apr 22.

Authors

Xueqiang Li¹, Christopher P Guise², Rana Taghipouran³, Yuliana Yosaatmadja⁴, Amir Ashoorzadeh³, Woo-Kyong Paik⁴, Christopher J Squire⁵, Shuang Jiang¹, Jinfeng Luo⁶, Yong Xu⁶, Zheng-Chao Tu⁶, Xiaoyun Lu⁷, Xiaomei Ren⁷, Adam V Patterson⁸, Jeff B Smaill⁹, Ke Ding¹⁰

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 2 / metabolism
Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 3 / metabolism
Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 4 / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
FGFR1 protein, human
FGFR2 protein, human
FGFR3 protein, human
FGFR4 protein, human
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 2
Receptor, Fibroblast Growth Factor, Type 3
Receptor, Fibroblast Growth Factor, Type 4