Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion.

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Carmi C, Cavazzoni A, Vezzosi S, Bordi F, Vacondio F, Silva C, Rivara S, Lodola A, Alfieri RR, La Monica S, Galetti M, Ardizzoni A, Petronini PG, Mor M

Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion.

J Med Chem. 2010 Mar 11;53(5):2038-50. doi: 10.1021/jm901558p.

PubMed ID
20151670 [ View in PubMed
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Abstract

Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-c arboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PD-168393Epidermal growth factor receptorIC 50 (nM)1.69N/AN/ADetails
PD-168393Epidermal growth factor receptorIC 50 (nM)152N/AN/ADetails
PD-168393Epidermal growth factor receptorIC 50 (nM)12N/AN/ADetails