MK-5108

In colorectal cancer, RAS and BRAF are major mutation points in the RAS-MAPK signaling pathway. These gene mutations are known to be important causes of resistance to anti-EGFR antibody therapies. Recently, it has been reported that Aurora kinase A (AURKA), one of the mitotic kinases, interacts with the EGFR-RAS-MAPK signaling pathway. In this study, we examined whether the combination of MK-5108 (AURKA inhibitor) and trametinib (MEK inhibitor) enhanced the antitumor effect for colon cancer cell lines. The combination of MK-5108 and trametinib showed synergistic enhancements of antitumor effect in three colon cancer cell lines harboring KRAS or BRAF mutation. Cell cycle analysis showed induction of G2/M and G1 arrests by MK-5108 and trametinib, respectively, and the potential enhancement of G1 arrest with the two drug combination. The addition of MK-5108 to trametinib enhanced the suppression of p-ERK and other G1/S progression-related proteins expression. In HCT116 cells, harboring wild-type TP53, the combination therapy induced more potent cell proliferation suppression and apoptosis induction than in TP53 knockout cells. These were related to potential enhancement of p53 expression and caspase activation. In conclusion, the combination of MK-5108 and trametinib may synergistically inhibit tumor cell division with or without TP53 mutation, and with either KRAS or BRAF mutation. Furthermore, the combination therapy could be more effective in wild-type TP53 cells.

The Aurora A kinase (AAK) protein controls spindle assembly and promotes cell divisions in various diseases including cancer.In the present study, allosteric inhibition of AAK protein through different advanced computational screening approaches is employed to target AAK's allosteric inhibition-modulation.Precisely, extensive computational techniques including allosteric binding sites recognition of AAK protein, fingerprint-based similarity search, multi-step mol. docking through AutoDock Vina and PLANTS, and a 100 ns mol. dynamics (MD) simulations studies were carried out followed by the calculation of binding free energy with MM-GBSA based approaches, has been employed for identification of potential allosteric inhibitors-modulators of AAK protein.The study outcome highlighted that all three identified small mol. chem. entities exhibit strong binding interaction affinity in both the docking analyses at the allosteric domain of AAK protein and also greater interaction stability in comparison to the considered standard compoundIn addition, all identified three screened hits also show acceptable pharmacokinetics and medicinal chem. properties, which certainly dictates their potentiality for becoming good drug-like compounds for inhibiting-modulating the activity of AAK protein binds with similar amino acids of the allosteric domain of AAK protein with selected three compoundsAll the selected mols. were found to show an acceptable ADMET profile.Moreover, the MM-GBSA-based binding energy was found to be in the range of -8 to -35 Kcal/mol, which showed a strong association between proposed mols. and AAK protein.Comprehensive computational approach shows that the selected proposed three inhibitors of AAK protein are the best candidates as potential inhibitors.