Novel Irreversible Epidermal Growth Factor Receptor Inhibitors by Chemical Modulation of the Cysteine-Trap Portion

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• 作者：Caterina Carmi ; Andrea Cavazzoni ; Stefano Vezzosi ; Fabrizio Bordi ; Federica Vacondio ; Claudia Silva ; Silvia Rivara ; Alessio Lodola ; Roberta R. Alfieri ; Silvia La Monica ; Maricla Galetti ; Andrea Ardizz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：March 11, 2010
• 年：2010
• 卷：53
• 期：5
• 页码：2038-2050
• 全文大小：1096K
• 年卷期：v.53,no.5(March 11, 2010)
• ISSN：1520-4804

文摘

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-carboxamide (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.