Discovering the inhibition of YAP/TEAD Hippo signaling pathway via new pyrazolone derivatives: synthesis, molecular docking and biological investigations

Heterocyclic compounds play a crucial role in the drug discovery process and development due to their significant presence and importance. Here, we report a comprehensive analysis of new pyrazolone derivatives, prepared according to a clear-cut, uncomplicated procedure. The pyrazolone derivatives were thoroughly characterized using various methods, such as elemental analysis, NMR, and FT-IR. The molecular docking interactions between the new pyrazolone derivatives and YAP/TEAD target protein observed that compound 4 had the top-ranked binding energy towards YAP/TEAD with a value equal to - 9.670 kcal/mol and this theoretically proves its inhibitory efficacy against YAP/TEAD Hippo signaling pathway. Besides, compound 4 showed the best IC₅₀ against HCT-116, HepG-2, and MCF-7 (in-vitro) with IC₅₀ 7.67 ± 0.5, 5.85 ± 0.4, and 6.97 ± 0.5 μM, respectively which confirmed our results towards suppressing YAP/TEAD protein (in-silico) compared with the IC₅₀ of Sorafenib (SOR) reference chemotherapeutic drug 5.47 ± 0.3, 9.18 ± 0.6 and 7.26 ± 0.3 μM, respectively. Also, compound 4 showed no cytotoxic effects against human lung fibroblast normal cell line (WI-38) and its pharmacokinetics were elucidated theoretically using ADMET compared with SOR which observed highly toxic effects on normal cells with IC₅₀ equal to 20.27 ± 0.45 μM. Additionally, compound 4 clarified a powerful antioxidant scavenging activity against DPPH free radicals (in-vitro). Conclusively, newly synthesized pyrazolone derivative 4 could be used as Anticancer candidate via inhibiting the YAP/TEAD mediated Hippo signaling pathway.

ADMET; Antioxidant; Hippo signaling pathway; Molecular docking; Pyrazolone.