Refinement of covalent EGFR inhibitor AZD9291 to eliminate off-target activity. (22nd June 2021)

• Record Type: Journal Article
• Authors: Bouffard, Elise; Zaro, Balyn W.; Dix, Melissa M.; Cravatt, Benjamin; Wong, Chi-Huey
• Is Part Of: Tetrahedron letters. Volume 74(2021)
• Publication Date: 2021-06-22
• Subjects: EGFR tyrosine kinase inhibitor -- Chemical proteomic analysis -- Proteomic reactivity -- Lysosome -- Covalent inhibitors -- Analogs synthesis; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2021.153178
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Off-target activity of EGFR tyrosine kinase inhibitor AZD9291. Chemical proteomic analysis of AZD9291 analogs. Reduction of off-target activity with retention of T790M-EGFR inhibition. Abstract: Non-small-cell lung cancer (NSCLC) is a major disease that accounts for 85% of all lung cancer cases which claimed around 1.8 billion lives worldwide in 2020. Tyrosine kinase inhibitors (TKIs) that target EGFR have been used for the treatment of NSCLC, but often develop drug resistance, and the covalent inhibitor AZD9291 has been developed to tackle the problem of drug resistance mediated by the T790M EGFR mutation; however, there is a side effect of hyperglycemia that may be due to off-target activity. This study examines analogs of AZD9291 by chemical proteomics, identifying analogs that maintain T790M-EGFR engagement while showing reduced cross-reactivity with off-targets.