Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Mutated epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC).
• The EGFR T790M mutation confers resistance to existing EGFR inhibitors like gefitinib and erlotinib.
• Developing novel inhibitors is crucial for overcoming acquired resistance in NSCLC treatment.

Purpose of the Study:

• To design and synthesize novel, potent, and selective EGFR inhibitors targeting the T790M mutation.
• To explore structure-activity relationships for optimizing inhibitor efficacy.
• To evaluate the anti-cancer activity of new compounds in preclinical models.

Main Methods:

• Structure-based drug design approach.
• Iterative structure-activity relationship (SAR) studies.
• In vitro kinase and cellular assays.
• In vivo efficacy studies using a human NSCLC xenograft model.

Main Results:

• Identified potent and selective EGFR inhibitors, compounds 19e and 19h.
• Compounds 19e and 19h demonstrated a unique binding mode distinct from other third-generation inhibitors.
• In vivo studies showed dose-dependent tumor growth suppression by 19e and 19h without observable toxicity.

Conclusions:

• Compounds 19e and 19h are promising drug candidates for EGFR T790M-mutated NSCLC.
• The structure-based design strategy successfully yielded potent and selective inhibitors.
• These novel inhibitors offer a potential therapeutic strategy for patients resistant to current treatments.