Discovery of Gö6976-related potent reversible EGFR T790M inhibitors.

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Discovery of Gö6976-related potent reversible EGFR T790M inhibitors. Discovery of Gö6976-related potent reversible EGFR T790M inhibitors. A, in vitro inhibition of recombinant EGFR autophosphorylation by Gö6976 or erlotinib. Recombinant EGFR wild-type, T790M, or L858R/T790M was phosphorylated by addition of ATP for 15 minutes in the presence of the indicated concentrations of Gö6976 or erlotinib. Immunoblots show autophosphorylated tyrosine residues in EGFR and total EGFR. B, chemical structures of Gö6976 and the structurally related Cep-701 and PKC412 inhibitors. C, comparison of Cep-701 and PKC412 for their inhibitory activities on EGFR T790M. Each recombinant EGFR protein was subjected to an autophosphorylation assay in the presence of ATP with Cep-701 or PKC412 for 15 minutes. D, viability assay of NCI-H1975 or NCI-H322 cells treated with Gö6976, Cep-701, PKC412 or erlotinib. NCI-H1975 or NCI-H322 cells were treated with various concentrations of the indicated inhibitors for 72 hours. Error bars, mean ± SEM. pTyr, phosphorylated tyrosine. Ho-June Lee et al. Cancer Discovery 2013;3:168-181 ©2013 by American Association for Cancer Research