Discovery of a novel Her-1/Her-2 dual tyrosine kinase inhibitor for the treatment of Her-1 selective inhibitor-resistant non-small cell lung cancer.

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Cha MY, Lee KO, Kim JW, Lee CG, Song JY, Kim YH, Lee GS, Park SB, Kim MS

Discovery of a novel Her-1/Her-2 dual tyrosine kinase inhibitor for the treatment of Her-1 selective inhibitor-resistant non-small cell lung cancer.

J Med Chem. 2009 Nov 12;52(21):6880-8. doi: 10.1021/jm901146p.

PubMed ID
19888761 [ View in PubMed
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Abstract

A novel series of (S)-1-acryloyl-N-[4-(arylamino)-7-(alkoxy)quinazolin-6-yl]pyrrolidine-2-carboxami des were synthesized and evaluated as Her-1/Her-2 dual inhibitors. In contrast to the Her-1 selective inhibitors, our novel compounds are irreversible inhibitors of Her-1 and Her-2 tyrosine kinases with the potential to overcome clinically relevant, mutation-induced drug resistance. The selected compounds (19c, 19d) showed excellent EGFR inhibition activity even toward the T790M mutation of Her-1 tyrosine kinase with excellent selectivity. The excellent pharmacokinetic profiles of these compounds in rats and their robust in vivo efficacy in an A431 xenograft model clearly demonstrate that they merit further investigation as novel therapeutic agents for EGFR-targeting treatment of solid tumors, especially Her-1 selective inhibitor-resistant non-small cell lung cancer.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ErlotinibEpidermal growth factor receptorIC 50 (nM)>1000N/AN/ADetails
LapatinibEpidermal growth factor receptorIC 50 (nM)52N/AN/ADetails
LapatinibReceptor tyrosine-protein kinase erbB-2IC 50 (nM)36N/AN/ADetails