Epidermal growth factor receptor (EGFR) is a tyrosine kinase with a key role in cell
proliferation, death and differentiation. Mutations in EGFR, including substitution of Thr790 by
methionine and Leu858 by arginine (T790M/L858R), lead to a lung cancer that is resistant against first
generation inhibitors. In fact, second generation inhibitors were developed, but they proved to have
had severe side effects because of the significant potency to suppress the wild type protein just as
much. To resolve the problem, a step-by-step rational virtual screening was employed over almost
sixty million compounds of PubChem Compound Database to filter out selective inhibitor(s) of
T790M/L858R subtype. Consequently, the compound CID 133077 was observed, an active metabolite of Axitirome and
also a cholesterol lowering prodrug. Selecting this compound can be explained by the oxamic acid part of molecule.
Hence, administration of Axitirome or other compounds which contain oxamic acid is suggested in cases with EGFR
T790M/L858R drug resistance.
Keywords: EGFR, rational virtual screening, docking studies, molecular dynamic simulations, pharmacophore search,
Axitirome, CID 133077.
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