Design, synthesis, and biological evaluation of novel aminopyrimidine derivatives as EGFR inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors like Osimertinib poses a significant challenge in non-small cell lung cancer (NSCLC) treatment.
• This resistance limits the long-term therapeutic efficacy of current targeted therapies, necessitating the development of novel therapeutic agents.

Purpose of the Study:

• To design and synthesize novel aminopyrimidine-based compounds targeting resistant forms of EGFR.
• To evaluate the inhibitory potential of these compounds against specific EGFR mutations, including EGFR^{L858R/T790M/C797S}.

Main Methods:

• Utilized Brigatinib, an EGFR^{L858R/T790M/C797S} inhibitor, as a reference compound for structural design.
• Synthesized a library of 24 target compounds featuring an aminopyrimidine core structure.
• Assessed the inhibitory activity of the synthesized compounds against EGFR^{L858R/T790M/C797S} and Ba/F3-EGFR^{L858R/T790M/C797S} cells.

Main Results:

• Compound IIB-5 demonstrated potent inhibition of EGFR^{L858R/T790M/C797S} with an IC₅₀ of 18.81 nM.
• IIB-5 exhibited strong inhibitory activity against Ba/F3-EGFR^{L858R/T790M/C797S} cells, achieving an IC₅₀ of 97.12 nM.
• Compound IIB-5 showed a five-fold increase in potency compared to Brigatinib against the tested cell line.

Conclusions:

• The novel aminopyrimidine compound IIB-5 is a potent inhibitor of EGFR^{L858R/T790M/C797S}, effectively targeting a key mutation driving resistance.
• IIB-5 offers a promising lead compound for the development of next-generation EGFR inhibitors to overcome therapeutic resistance in NSCLC.
• This study provides a valuable foundation for further research into novel EGFR inhibitors for refractory non-small cell lung cancer.