Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Fibroblast Growth Factor Receptors (FGFRs) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling pathways are frequently implicated in various cancers, promoting tumor angiogenesis.
• Upregulation of FGF-2 is linked to resistance against VEGFR2 inhibitors, with FGFR activation serving as a compensatory angiogenesis mechanism.
• Dual inhibition of VEGFR2 and FGFR1 offers a strategy to overcome resistance and significantly inhibit tumor growth.

Purpose of the Study:

• To design and synthesize novel 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors.
• To evaluate the inhibitory activity and antiproliferative effects of these compounds.
• To investigate the binding modes of the lead compound with VEGFR2 and FGFR1 via molecular docking.

Main Methods:

• Molecular hybridization strategy was employed to design and synthesize pyrimidine derivatives.
• In vitro enzymatic assays were used to assess inhibitory activities against VEGFR2 and FGFR1.
• Antiproliferative activity was evaluated against A549 and KG-1 cell lines.
• Molecular docking studies were performed to understand the binding interactions.

Main Results:

• Compound 8b, 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea, exhibited potent inhibition against VEGFR2 (82.2%) and FGFR1 (101.0%) at 10 μM.
• Compound 8b demonstrated moderate antiproliferative effects on A549 and KG-1 cell lines.
• Molecular docking provided insights into the binding mechanisms of compound 8b with VEGFR2 and FGFR1.

Conclusions:

• The synthesized pyrimidine derivatives show potential as dual VEGFR2/FGFR1 inhibitors.
• Compound 8b is a promising lead candidate for further optimization in cancer therapy.
• These findings support the development of dual inhibitors to overcome resistance in cancer treatment.