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

Sci Rep. 2024 Nov 21;14(1):28859. doi: 10.1038/s41598-024-79992-x.

Abstract

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.

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Hippo Signaling Pathway
  • Humans
  • Molecular Docking Simulation*
  • Protein Serine-Threonine Kinases* / antagonists & inhibitors
  • Protein Serine-Threonine Kinases* / metabolism
  • Pyrazolones* / chemistry
  • Pyrazolones* / pharmacology
  • Signal Transduction* / drug effects
  • TEA Domain Transcription Factors
  • Transcription Factors* / antagonists & inhibitors
  • Transcription Factors* / metabolism
  • YAP-Signaling Proteins

Substances

  • Pyrazolones
  • Transcription Factors
  • Protein Serine-Threonine Kinases
  • pyrazolone
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • TEA Domain Transcription Factors