Refinement of Covalent EGFR Inhibitor AZD9291 to Eliminate Off-target Activity
Elise Bouffard1, Balyn W Zaro1, Melissa M Dix1
1Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037.
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.
Insights
Researchers developed new non-small cell lung cancer (NSCLC) drugs targeting T790M-EGFR mutations. These analogues maintain efficacy while reducing side effects like hyperglycemia by minimizing off-target activity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Non-small cell lung cancer (NSCLC) represents 85% of lung cancer cases, a leading cause of cancer-related mortality.
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard NSCLC treatments but face challenges with drug resistance.
- The T790M mutation confers resistance to earlier TKIs, necessitating targeted therapies like AZD9291, which can cause hyperglycemia due to off-target effects.
Purpose of the Study:
- To identify novel analogues of AZD9291 with preserved efficacy against T790M-mutated EGFR.
- To reduce off-target activity and associated side effects, specifically hyperglycemia.
- To explore structure-activity relationships for improved TKI drug design.
Main Methods:
- Chemical proteomics was employed to screen and identify AZD9291 analogues.
- In vitro assays were used to assess T790M-EGFR engagement.
- Off-target cross-reactivity profiling was performed to evaluate selectivity.
Main Results:
- Several AZD9291 analogues demonstrated potent inhibition of T790M-EGFR.
- Identified analogues exhibited significantly reduced cross-reactivity with known off-targets compared to AZD9291.
- The findings suggest a potential for improved therapeutic index.
Conclusions:
- Novel AZD9291 analogues can effectively target T790M-EGFR while mitigating off-target associated hyperglycemia.
- This research provides a foundation for developing next-generation EGFR inhibitors with enhanced safety profiles for NSCLC treatment.
- Chemical proteomics is a valuable tool for optimizing drug design and minimizing adverse effects.
