Refinement of covalent EGFR inhibitor AZD9291 to eliminate off-target activity

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. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

Non-small-cell lung cancer (NSCLC) is a major disease causing 1.8 billion deaths worldwide, with tyrosine kinase inhibitors (TKIs) being used for treatment but facing drug resistance and side effects. This study identified analogs of AZD9291 through chemical proteomics that maintained engagement with T790M-EGFR while reducing cross-reactivity with off-targets.