Refametinib

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.

DNA methyltransferase 3A (DNMT3A) has been associated with the occurrence or progression of various tumors, including gastric cancer. However, the role of DNMT3A in the efficacy of immune-cell infiltration in the tumor microenvironment and immunotherapy in gastric cancer remains less explored. DNMT3A expression level was analyzed using TIMER 2.0, Sangerbox 3.0, and The Cancer Genome Atlas database and further verified by immunohistochemical staining and RT-qPCR. The UALCAN, chi-square test, and Kaplan–Meier plotter databases were performed to assess the correlation of DNMT3A with clinicopathological characteristics and prognosis. The GeneMANIA database, STRING database, and R package were used to construct a DNMT3A co-expression gene network. Gene set enrichment analysis was used to identify the signaling pathways related to DNMT3A expression. The correlations between DNMT3A and cancer immune infiltrates were investigated using TIMER 2.0, Sangerbox 3.0, Kaplan–Meier Plotter, R package, and TISIDB databases. The TISIDB database and R package were used to construct the correlation between DNMT3A and immunomodulators and Immune cell Proportion Score. The association of DNMT3A expression with tumor mutational burden (TMB), microsatellite instability, and tumor dryness was evaluated using the TMB function of the R package, TIMER 2.0. Finally, the biological function of DNMT3A in gastric cancer cells was further assessed by CCK-8, cloning formation, and transwell assay. DNMT3A expression was remarkably upregulated in gastric cancer. The high expression of DNMT3A was associated with poor clinical features and poor survival in patients with gastric cancer. Moreover, gene set enrichment analyses showed that DNMT3A and its related genes were involved in various pathways that promoted cancer occurrence and progression by influencing the tumor microenvironment. Finally, DNMT3A was significantly related to tumor-infiltrating immune cells, immunomodulators, TMB, microsatellite instability, and immune checkpoints in gastric cancer. Moreover, knockdown of DNMT3A reduced the proliferation and migration of gastric cancer cells. Our findings highlight the potential of DNMT3A as a prognosis biomarker and an immunotherapeutic target for gastric cancer.