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Refinement of Covalent EGFR Inhibitor AZD9291 to Eliminate Off-target Activity.

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 analogues of AZD9291 by chemical proteomics, identifying analogues that maintain T790M-EGFR engagement while showing reduced cross-reactivity with off-targets.

SUBMITTER: Bouffard E

PROVIDER: S-EPMC8577418 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Refinement of Covalent EGFR Inhibitor AZD9291 to Eliminate Off-target Activity.

Bouffard Elise E Zaro Balyn W BW Dix Melissa M MM Cravatt Benjamin B Wong Chi-Huey CH

Tetrahedron letters 20210513

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 a ...[more]

PMID: 34764521

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Acquired resistance to mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling

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