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.

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft-tissue sarcoma that develops sporadically or in patients with neurofibromatosis type 1 (NF1). Its development is marked by the inactivation of specific tumor suppressor genes (TSG): NF1, CDKN2A, and SUZ12/EED (polycomb repressor complex 2). Each TSG loss can be targeted by particular drug inhibitors, and we aimed to systematically combine these inhibitors, guided by TSG inactivation status, to test their precision medicine potential for MPNSTs.

We performed a high-throughput screening in 3 MPNST cell lines testing 14 MEK inhibitors (MEKi), 11 cyclin-dependent kinase 4/6 inhibitors (CDKi), and 3 bromodomain inhibitors (BETi) as single agents and 147 pairwise co-treatments. Best combinations were validated in nine MPNST cell lines, and three were tested in one sporadic and one NF1-associated patient-derived orthotopic xenograft (PDOX) MPNST mouse model. A final combination of the three inhibitor classes was tested in the same PDOX models.

A high degree of redundancy was observed in the effect of compounds of the same inhibitory class, individually or in combination, and responses matched with TSG inactivation status. The MEKi–BETi (ARRY-162 + I-BET151) co-treatment triggered a reduction in half of the NF1-related MPNST PDOXs and all the sporadic tumors, reaching 65% reduction in tumor volume in the latter. Remarkably, this reduction was further increased in both models combining the three inhibitor classes, reaching 85% shrinkage on average in the sporadic MPNST.

Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi–BETi CDKi triple treatment elicits a significant reduction of human MPNST PDOXs.