| Summary: | A series of novel 3-cyanopyridone/pyrazoline hybrids (<b>21–30</b>) exhibiting dual inhibition against EGFR and BRAF<sup>V600E</sup> has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds <b>28</b> and <b>30</b> demonstrated remarkable antiproliferative activity, boasting GI<sub>50</sub> values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAF<sup>V600E</sup> pathways. Compounds <b>28</b> and <b>30</b>, akin to Erlotinib, displayed promising anticancer potential. Compound <b>30</b> emerged as the most potent inhibitor against cancer cell proliferation and BRAF<sup>V600E</sup>. Notably, both compounds <b>28</b> and <b>30</b> induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds <b>28</b> and <b>30</b> to act as dual EGFR/BRAF<sup>V600E</sup> inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.
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