Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor

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.