Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Cancer Biology

Background:

• Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) are crucial in tumor progression, angiogenesis, and metastasis.
• Targeting these receptors offers a promising strategy for cancer therapy.

Purpose of the Study:

• Synthesize novel fused pyrazole derivatives.
• Evaluate their in vitro anticancer activity against HEPG2 human cancer cell lines.
• Assess their inhibitory potential against EGFR and VEGFR-2.

Main Methods:

• Synthesis of dihydropyrano[2,3-c]pyrazole, pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine, pyrazolo[3,4-d]pyrimidine, and pyrazolo[3,4-c]pyrazole derivatives.
• Anticancer activity evaluation using HEPG2 cell lines, with erlotinib and sorafenib as references.
• In vitro kinase inhibition assays for EGFR and VEGFR-2.
• Molecular docking studies.

Main Results:

• Seven synthesized compounds exhibited significantly higher anticancer activity (IC50 0.31–0.71 μM) compared to erlotinib (10.6 μM).
• Compound 3 demonstrated potent EGFR inhibition (IC50 = 0.06 μM), and compound 9 showed potent VEGFR-2 inhibition (IC50 = 0.22 μM).
• Compounds 9 and 12 displayed dual inhibition of both EGFR and VEGFR-2, supported by docking studies.

Conclusions:

• The synthesized fused pyrazole derivatives hold significant potential as anticancer agents.
• Compounds 3, 9, and 12 are promising candidates for further development targeting EGFR and/or VEGFR-2.
• The study validates the therapeutic potential of targeting EGFR and VEGFR-2 with novel pyrazole scaffolds.