Novel inhibitors of eukaryotic elongation factor 2 kinase: In silico, synthesis and in vitro studies

Novel etodolac derivatives as eukaryotic elongation factor 2 kinase (eEF2K) inhibitors for targeted cancer therapy

“…However, its 3D structure prediction using alphafold (v.2) is available at the UniProt (AF-000418-F1-model_v2). When we superimpose our 3D model 17 with the alphafold model, both models aligned well to each other for the ligand binding domain (i.e. regions of residue numbers 107 to 326).…”

“…2). 17,19 Thin layer chromatography (TLC) was used to observe the progress of the reaction. The reactions were performed with high yields.…”

“…[44][45][46] Recently, we demonstrated that several compounds containing a coumarin scaffold were effective as eEF2K inhibitors for targeting eEF2K in cancer models. [17][18][19][20][21] Therefore, we focused on identifying highly potent eEF2K inhibitors at low concentrations using a new core structure in cancer cells. Our findings showed that amide substituted pyranoindole derivatives are highly effective in inhibiting eEF2K and they could be used as potent eEF2K targeted anticancer candidates in the tumor models.…”

“…16 Because of the clinical significance of eEF2K and its potential as a molecular target for precision medicine, recently there has been significant interest in developing highly effective inhibitors for eEF2K for clinical translation. [17][18][19][20][21][22][23][24] However, development of effective inhibitors has been challenging due to the lack of data regarding the 3D crystal structure of eEF2K. eEF2K is not inhibited by the well-known pan kinase inhibitors such as staurosporine.…”

“…eEF2K is not inhibited by the well-known pan kinase inhibitors such as staurosporine. 16 To meet this challenge, recently we have developed and utilized the homology modeling [17][18][19] based on similarity of the kinase domain of eEF2K to its close relatives such as myosin heavy chain kinase 2 (MHCK-2) in the alphakinase family and focused on identifying eEF2K inhibitors with various core structures such as indoles, which are widely used in drug discovery studies because of their effective pharmacological properties. 25 Indole containing drugs such as indole alkaloids vincristine and vinblastine are used for the treatment of cancers like breast cancer and other cancers.…”