2. Academic Validation
  3. Identification of novel aminopyrimidine derivatives for the treatment of mutant NSCLC

Identification of novel aminopyrimidine derivatives for the treatment of mutant NSCLC

  • Eur J Med Chem. 2023 Dec 20:265:116074. doi: 10.1016/j.ejmech.2023.116074.
Liping Hu 1,  Shengmin Shi 1,  Xiaomeng Song 1,  Fangli Ma 1,  Oulian Ji 1,  Baohui Qi 2
Affiliations

Affiliations

  • 1 School of Bioengineering, Zunyi Medical University, Zhuhai, 519041, China; Key Laboratory of Biocatalysis&Chiral Drug Synthesis of Guizhou Province, Zunyi Medical University, Zunyi, 563000, China.
  • 2 School of Bioengineering, Zunyi Medical University, Zhuhai, 519041, China; Key Laboratory of Biocatalysis&Chiral Drug Synthesis of Guizhou Province, Zunyi Medical University, Zunyi, 563000, China. Electronic address: [email protected].
PMID: 38142512 DOI: 10.1016/j.ejmech.2023.116074
Abstract

Starting from the binding mode of allosteric EGFR inhibitor JBJ-04-125-02 and the key pharmacophore of the third-generation EGFR inhibitors, we designed and synthesized a novel series of EGFR inhibitors, represented by (R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindolin-2-yl)-2-phenylacetamide (6q). Docking study demonstrated that top compound 6q spanned orthosteric and allosteric sites of EGFR, and formed three key H-bonds with the residues Asp855, Lys745, and Met793 located in two sites. Biological evaluation indicated that compound 6q showed potential inhibitory activity against Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFRDel19/T790M/C797S cells, with IC50 values of 0.42 μM and 0.41 μM, respectively. Furthermore, compound 6q showed excellent activity against mutant NSCLC cell line NCI-H1975-EGFRL858R/T790M/C797S cells, with IC50 value of 0.82 μM which was superior to that of osimertinib (IC50 = 2.94 μM), JBJ-04-125-02 (IC50 = 3.66 μM), and coadministration of JBJ-04-125-02 and osimertinib (IC50 = 1.25 μM). Cell cycle arrest and cell Apoptosis assay indicated that compound 6q could promote Apoptosis of NCI-H1975-EGFRL858R/T790M/C797S cells at the concentration of 0.8 μM and no obvious cell cycle arrest was found.

Keywords

Allosteric site; Aminopyrimidine; EGFR; Inhibitors; NSCLC.

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