Identification of Potent and Novel Inhibitors against Dual specificity mitogen-activated protein kinase kinase 1 (MEK1)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, globally. Its high mortality rates hasn’t changed much in the last three decades and the overall survival is still less than 5 years. Therefore, there is an urgent need for novel therapeutics specifically developed for HNSCC. One of the most commonly altered oncogenic pathways is Ras-Raf-MEK-ERK signalling pathway. This pathway is downstream to EGFR and has been reported to be involved in radio resistance. MEK1 is a tyrosine/threonine protein kinase found in the MAP kinase (MAPK) signalling cascade which is constitutively expressed in approximately 30% of all the cancer types. It holds a very strategic position in the MAPK cascade. It is the only kinase which activates ERK ½ which is involved in several cellular pathways, both cytoplasmic as well as nuclear and has been found mutated in various cancers including HNSCC. Currently, there is no FDA approved inhibitor of MEK1 specifically against HNSCC. Therefore, designing more effective and specific MEK1 inhibitors could be a promising strategy in the treatment of HNSCC. We screened more than 400,000 compounds to select the two best candidate compounds, C387-1559 and G545-0469 using High Throughput Screening (HTS) of huge databases (National Cancer Institute (NCI), Life Chemicals, Chem Diversity and ChEMBL), and Molecular Dynamic Simulations. Both the selected compounds were further analysed at different concentrations by Biolayer Interferometry (BLI) technique for their real-time interaction with the MEK1 protein. The selected compounds were evaluated for their cytotoxic effect against different cancer cell lines. The IC50 values of the compounds C387-1559 and G545-0469 on human tongue squamous cell carcinoma cell line, CAL27, were 5µM and 6µM, respectively and on human prostate cancer cell line, DU145, were 14.77 µM, 54.38 µM, respectively at 72hrs. This data suggests higher efficiency of C387-1559 and G545-0469 on human head and neck squamous cell cancer than human prostate cancer. Overall, this study identified two novel inhibitors of MEK1 that can be used in the development of potential therapeutics against HNSCC.