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EGFR signaling is involved in multiple cellular processes including cell proliferation, differentiation and development, making this protein kinase one of the most valuable drug targets for the treatment of non–small cell lung carcinomas (NSCLC). Herein, we describe the design and synthesis of a series of potential covalent inhibitors targeting the catalytically conserved lysine (K745) of EGFR on the basis of Erlotinib, an FDA-approved first-generation EGFR drug. Different amine-reactive electrophiles were introduced at positions on the Erlotinib scaffold proximal to K745 in EGFR. The optimized compound 26 (as well as its close analog 30), possessing a novel arylfluorosulfate group (ArOSO₂F), showed excellent in vitro potency (as low as 0.19 nM in independent IC₅₀ determination) and selectivity against EGFR and many of its drug-resistant mutants. Both intact protein mass spectrometry (MS) and site-mapping …