Targeting EGFR mutants with non-cognate kinase inhibitors in non-small cell lung cancer

Considering that the human protein kinase family members share high conservation in both primary sequence and advanced structure, and a large number of small-molecule inhibitors have already been developed to target these different members, we herein are interested in whether certain existing inhibitors that were originally designed for other (cognate) kinases can also bind efficiently to (non-cognate) epidermal growth factor receptor (EGFR) mutants and simultaneously lie low affinity to wild-type EGFR. To explore this notion, a structure-based quantitative structure–activity relationship model was derived from 77 crystal structure-solved, affinity-known kinase–inhibitor complexes. We employed this model to profile a systematic interaction map of 2 cognate and 11 non-cognate kinase inhibitors with wild-type EGFR and its several important NSCLC-related mutants. As might be expected, the cognate inhibitors exhibited generally high affinity to both wild-type and mutant EGFR, while most non-cognate inhibitors have low binding potency for EGFR. However, few combinations of non-cognate inhibitors and EGFR mutants, such as TAE684 and T790M, SKI606 and L858R, and R406 and T790M, show a favorable interaction as compared to the same inhibitors with wild-type EGFR. A further kinase assay was performed to determine the inhibitory activities of compound TAE684, originally developed as a ALK kinase inhibitor, against wild-type and T790M mutant EGFR; it is revealed that the TAE684 inhibited the mutant with ~tenfold higher potency than the wild-type enzyme. This work would help to establish a new strategy for the new use of an old drug.