Modification of osimertinib to discover new potent EGFR^C797S-TK inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Acquired resistance to osimertinib in non-small cell lung cancer (NSCLC) is often driven by the EGFR C797S mutation.
• Currently, no approved inhibitors effectively overcome this resistance mechanism.

Purpose of the Study:

• To design, synthesize, and evaluate novel fourth-generation EGFR C797S-TK inhibitors based on the osimertinib scaffold.
• To identify a potent compound capable of overcoming osimertinib resistance.

Main Methods:

• Synthesis of phenylamino-pyrimidine derivatives.
• In vitro kinase inhibition assays against EGFR C797S mutant forms.
• Cell proliferation assays using engineered cell lines (BaF3-EGFR).
• In vivo efficacy studies in a xenograft mouse model.

Main Results:

• Compound Os30 demonstrated potent inhibition of EGFR Del19/T790M/C797S and EGFR L858R/T790M/C797S TK (IC50 values 18 nM and 113 nM).
• Os30 effectively inhibited proliferation, suppressed EGFR phosphorylation, induced G1 cell cycle arrest, and promoted apoptosis in resistant NSCLC cells.
• Os30 exhibited significant antitumor efficacy in vivo, with a 77.6% tumor growth inhibitory rate in a xenograft model.

Conclusions:

• Modification of the osimertinib scaffold can yield potent EGFR C797S-TK inhibitors.
• Compound Os30 represents a promising fourth-generation EGFR inhibitor for treating NSCLC with EGFR C797S mutations, addressing a critical unmet clinical need.