An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAFV600E inhibitors.

PMID 40056327 | PMCID PMC12638379 | DOI 10.1007/s11030-025-11127-4 · Molecular diversity · 2025 · View on PubMed ↗

Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC50 values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAFV600E. Compound 4e exhibited the highest inhibitory activities, with IC50 values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAFV600E, compared to the reference drugs erlotinib (IC50 0.06 ± 0.002 μM) and vemurafenib (IC50 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAFV600E. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAFV600E compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.