Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation.

The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC ₅₀ ) values of 2.7-63 μM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC ₅₀ of 2.0 and 0.9 μM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC ₅₀  = 1.7 μM). Notably, 6c inhibited both kinases, with IC ₅₀ values of 2.7 and 3.0 μM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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