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Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant
Marcel Günther1, Michael Juchum1, Gerhard Kelter2
1Eberhard Karls Universität Tübingen, Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
Abstract:
The treatment of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third-generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR.
Insights
New EGFR inhibitors overcome resistance in non-small-cell lung cancer (NSCLC) by targeting cysteine mutations. These novel drugs show promise for patients with acquired resistance to earlier treatments.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC) is a significant clinical challenge.
- Third-generation EGFR inhibitors, while effective against common mutations, face limitations due to acquired resistance mutations, particularly at the Cys797 residue.
- The Cys797 mutation in EGFR confers resistance to existing covalent inhibitors, leading to treatment failure and tumor relapse.
Purpose of the Study:
- To develop novel EGFR inhibitors that overcome resistance mediated by the Cys797 mutation.
- To design inhibitors with potent activity against EGFR mutations, including the L858R/T790M/C797S triple mutant.
- To explore both irreversible and reversible inhibitor strategies with strong noncovalent binding properties.
Main Methods:
- Development of a new class of mutant-selective EGFR inhibitors.
- Characterization of inhibitor binding properties, focusing on noncovalent interactions.
- Evaluation of inhibitory activity against EGFR mutants, including those with the Cys797 substitution.
- Assessment of efficacy in preclinical models of NSCLC with acquired resistance.
Main Results:
- A new generation of irreversible and reversible EGFR inhibitors was successfully developed.
- These novel inhibitors exhibit strong noncovalent binding to the target enzyme.
- High inhibitory activities were observed against the L858R/T790M/C797S EGFR mutant, which confers resistance to prior therapies.
- The developed compounds demonstrate potential to overcome Cys797-mediated resistance.
Conclusions:
- The newly developed EGFR inhibitors are effective against challenging resistance mutations, including Cys797.
- These compounds represent a promising therapeutic strategy for NSCLC patients who have relapsed due to acquired resistance.
- Noncovalent binding strategies offer a viable approach to overcome resistance to covalent EGFR inhibitors.
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