Refametinib

Epoxide hydrolase-4 (EPHX4) belongs to the epoxide hydrolase enzyme family, but its biological function remains unclear, especially its potential involvement in the development of pancreatic tumours. This research sought to examine the function of EPHX4 in pancreatic adenocarcinoma (PAAD).

The expression of EPHX4 across cancers was examined through The Cancer Genome Atlas (TCGA). Bioinformatics was employed, leveraging multiple databases to investigate EPHX4 gene expression in pancreatic cancer and its association with survival prognosis, functional enrichment, immune infiltration, tumour mutation load, and drug sensitivity, among other variables. To evaluate EPHX4 expression in PAAD cells, Western blotting and reverse transcription quantitative PCR were used. A series of in vitro functional experiments was performed to assess the proliferation, migration, and invasion of PAAD cells.

EPHX4 expression was markedly elevated in a number of malignancies, including PAAD, and was associated with patient sex, clinical stage, and metastasis to the lymph nodes. High EPHX4 expression was significantly associated with a worse outcome in PAAD patients. According to functional and enrichment studies, EPHX4 is involved in many signalling pathways linked to cancer. The study of immune infiltration revealed that EPHX4 was connected to the existence of a variety of immune cells inside the tumour. Our study revealed that EPHX4 knockdown significantly decreased PAAD cell migration, proliferation, and invasion.

EPHX4 is highly expressed in PAAD and independently predicts poor survival. Functional experiments demonstrate its tumor-promoting effects. Its involvement in multiple cancer-related signaling pathways and immune regulation mechanisms highlights the dual prognostic and therapeutic potential of EPHX4 in PAAD.

This study explores the therapeutic potential of novel MEK1/2 inhibitors targeting the MAPK pathway, emphasizing their critical role in cancer progression. An integrated computational approach, including molecular docking, pharmacophore modeling, molecular dynamics simulations, and DFT analysis, was employed to evaluate the binding affinity, stability, and pharmacological properties of FDA‐approved and experimental compounds. Structural validation of MEK1 (PDB ID: 1S9J) and MEK2 (PDB ID: 1S9I) revealed z‐scores of −6.89 and −7.13, respectively, with 90.6% and 86.7% of residues in the most favored regions, confirming the reliability of the protein models. Docking studies identified RO5126766 as a lead compound, exhibiting binding energies of −10.1 kcal/mol with MEK1 and −9.5 kcal/mol with MEK2. Molecular dynamics simulations further demonstrated the stability of the RO5126766–MEK1 and RO5126766–MEK2 complexes, with RMSD values ranging from 0.95 to 4.22 Å. The in vitro anticancer assays highlighted the exceptional potency of RO5126766, with IC50 values of 12.87 ± 98.36 nM against MCF‐7 (hormone receptor‐positive breast cancer), 15.08 ± 94.36 nM against MDA‐MB‐231 (triple‐negative breast cancer), and 60.89 ± 70.58 nM against A549 (lung cancer). ADMET analysis confirmed high gastrointestinal absorption, favorable drug‐likeness, and lack of blood‐brain barrier permeability. In addition, DFT studies indicated an optimal HOMO–LUMO energy gap (0.15816 eV), chemical hardness (0.16189 eV), and strong molecular interactions corroborated by MEP analysis. Collectively, these findings establish RO5126766 as a potent and selective MEK1/2 inhibitor, demonstrating significant potential as a targeted therapeutic agent for aggressive and treatment‐resistant cancers.