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

• Published in: European journal of medicinal chemistry 2017-07, Vol.135, p.531-543
• Main Authors: Li, Xueqiang, Guise, Christopher P., Taghipouran, Rana, Yosaatmadja, Yuliana, Ashoorzadeh, Amir, Paik, Woo-Kyong, Squire, Christopher J., Jiang, Shuang, Luo, Jinfeng, Xu, Yong, Tu, Zheng-Chao, Lu, Xiaoyun, Ren, Xiaomei, Patterson, Adam V., Smaill, Jeff B., Ding, Ke
• Format: Article
• Language: English
• Subjects: 2-Oxo-3,4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; FGFR; Humans; Irreversible inhibitor; 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
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.04.049

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. Structural optimization of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives yielded new selective FGFR inhibitors. Compound 2l covalently inhibited FGFR1-3 kinase with IC50 values of 1.06, 0.84 and 5.38 nM, respectively. Compound 2l significantly suppressed the growth of FGFR-amplified cancer cell lines and was less potent against FGFR-negative cancer cell lines and human normal liver HL7702 cells. Western blot analysis revealed that 2l dose-dependently inhibited the phosphorylation of FGFR in SUM52 cells bearing amplified-FGFR2 at nanomolar concentrations. [Display omitted] •2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were optimized as new selective covalent FGFR inhibitors.•Compound 2l potently inhibited the FGFRs kinases and proliferation of FGFR-amplified cancer cell lines with low nM IC50 values.