Discovery of selective irreversible inhibitors for EGFR-T790M

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• ATP-competitive kinase inhibitors targeting the epidermal growth factor receptor kinase (EGFR) provide temporary benefits for non-small cell lung cancer patients with EGFR mutations.
• Acquired resistance, often due to the T790M mutation, limits the long-term efficacy of these therapies.

Purpose of the Study:

• To discover novel covalent EGFR kinase inhibitors with selectivity for the T790M resistance mutation over wild-type EGFR.
• To identify potent and selective compounds for the treatment of EGFR-mutated non-small cell lung cancer.

Main Methods:

• Library screening was employed to identify initial hit compounds.
• Structure-activity relationship (SAR) studies, guided by cellular proliferation assays dependent on mutant EGFR, were conducted.
• Covalent inhibitors were designed to target specific mutations in EGFR.

Main Results:

• A series of novel covalent EGFR kinase inhibitors were discovered.
• Compounds demonstrated selectivity for the T790M resistance mutation compared to wild-type EGFR.
• A representative compound, 3i, was identified through systematic optimization.

Conclusions:

• Novel covalent EGFR inhibitors targeting the T790M mutation offer a potential therapeutic strategy for overcoming resistance in non-small cell lung cancer.
• Compound 3i represents a promising candidate for further development in treating EGFR-mutated lung cancer.