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Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells
Published on: May 9, 2025
Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor
Bryan K Chan, Emily J Hanan, Krista K Bowman
1Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
Abstract:
Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746-750, T790M/L858R, and T790M/del746-750) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del746-750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746-750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.
Insights
Researchers developed new reversible, noncovalent inhibitors for epidermal growth factor receptor (EGFR) mutations, including T790M, which causes resistance to cancer drugs. These inhibitors show promise for treating non-small-cell lung cancer.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- First-generation epidermal growth factor receptor (EGFR) inhibitors are effective against EGFR-mutant non-small-cell lung cancer (NSCLC).
- Acquired resistance to these therapies often arises from a secondary T790M mutation in the EGFR binding site.
- Developing inhibitors that overcome this resistance is crucial for improving NSCLC treatment outcomes.
Purpose of the Study:
- To optimize a series of reversible, noncovalent inhibitors targeting both activating and T790M-resisted EGFR mutants.
- To identify lead compounds with potent activity against a spectrum of EGFR mutations, including single and double mutants.
- To ensure favorable in vitro ADME-PK properties for potential clinical development.
Main Methods:
- Structure-guided modifications of a noncovalent double mutant-selective EGFR inhibitor (compound 2).
- Introduction of activity against single EGFR mutants (L858R, del746-750) through iterative chemical optimization.
- In vitro assessment of cellular activity, target engagement, and ADME-PK properties of optimized compounds, including lead inhibitor 21.
Main Results:
- Successful optimization yielded reversible, noncovalent inhibitors with pan-mutant EGFR activity.
- Compound 21 demonstrated excellent cellular activity against single (L858R, del746-750) and double (T790M/L858R, T790M/del746-750) EGFR mutants.
- In vivo target engagement and suitable ADME-PK profiles were confirmed for the lead inhibitor.
Conclusions:
- Reversible, noncovalent inhibitors targeting a range of EGFR mutations, including resistance mutations, have been developed.
- These novel inhibitors offer a complementary approach to existing covalent therapies for EGFR-mutant NSCLC.
- The lead compound 21 warrants further investigation for its therapeutic potential in NSCLC treatment.
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