Synthesis and evaluation of novel non-covalent binding quinazoline glycoside derivatives targeting the L858R and T790M variants of EGFR

Abstract

A series of novel quinazoline glycoside derivatives were designed, synthesized, and evaluated for their inhibition activities against EGFR-WT, EGFR/L858R/T790M, and skin epidermoid carcinoma cell line (A431). Several L-rhamnose derivatives were found to be as efficient as the irreversible inhibitor HKI-272 or BIBW2992 in inhibiting EGFR/T790M/L858R. Molecular dynamic simulations indicated that the saccharide group plays a significant role in stabilization of the quinazoline glycoside derivative through the hydrogen bonding with several polar residues at the edge of the ATP-binding cleft.