In silico guided development of imine-based inhibitors for resistance-deriving kinases

Two major mechanisms involved in resistant NSCLC (non-small cell lung cancer) include secondary acquired mutation in EGFR (epidermal growth factor receptor), that is, EGFR T790M and amplification of c-MET (hepatocyte growth factor receptor). Thus, already established pharmacophore models of EGFR T790M and c-MET were employed to filter-out an in-house database. Further fitness score led to the selection of imino-pyrimidine scaffold. Followed by sketching of imino-pyrimidine derivatives having varied aryl substitutions, which were then docked and subjected to molecular dynamic simulations, to study the orientations and conformations of the designed molecules in the catalytic domain. Molecules with hydrophobic interaction with mutant residue M790 were selected. Finally, MM-GBSA (Molecular Mechanics‐Generalized Born Surface Area) calculations were performed, to study the effect of substitutions on the binding affinity of the double mutant EGFR towards these small molecules. Finally, the designed compounds were synthesized and evaluated for their kinase inhibitory potential using in-vitro experiments. Two compounds were found to possess sub-micromolar range inhibitory potential against EGFR (T790M), while one of the compound showed significant selective inhibitory potential against c-MET. Additionally, one compound was found to possess significant dual inhibitory potential against these target kinases.

Communicated by Ramaswamy H. Sarma