Design of ERK2 inhibitors for cancer therapy

Constitutive activation of ERK1/2 pathway drives the proliferation and survival of many cancer cell types. Therefore, the new approaches, i.e. small molecular weight compounds targeting directly hyperactivated ERK 1/2, are widely explored as anticancer compounds. Recently, new molecules based on a 1,1-dioxido-2,5-dihydrothiophen-3-yl 4-benzenesulfonate scaffold (targeting the FRS domain of ERK2) were synthesized. These new molecules, indicated as compounds 4 and 6, contain modifications of the arylamine substituent at the 4-position of the heterocyclic scaffold. To gain insight into molecular mechanisms of their activity, the study was focused on the exploration of potential interaction of these new compounds with ERK2 by means of in silico study, i.e. molecular docking. The docking procedure was carried out within both substrate docking sites, DRS and FRS, and ATP binding sites, and by means of Molecular Operating Environment (MOE) system. The 4gt3, 
high-resolution ERK2 structure available in the Protein Data Bank (RCSB PDB) was chosen for this purpose. The analysis indicated that both compounds 4 and 6 bound with similar efficiency within both substrate docking sites, DRS and FRS, but not in the ATP binding site.