Insights into the overcoming EGFR Del19/T790M/C797S  mutation: A perspective on the 2-aryl-4-aminothienopyrimidine backbone

ChemMedChem. 2024 Feb 14:e202300634. doi: 10.1002/cmdc.202300634. Online ahead of print.ABSTRACTThe epithelial growth factor receptor signaling pathway has been proposed to benefit non-small cell lung cancer treatment. In this manuscript, we investigated the modification of 2-aryl-4-aminoquinazoline, the classical backbone of the fourth-generation EGFR inhibitors, in addition to obtaining a series of novel 2-aryl-4-aminothienopyrimidine derivatives (A1~A45), we also gained further understanding of the modification of this framework. The bioactivity of these compounds was evaluated and it's suggested that compound A9 could effectively inhibit the proliferation of A549 and H1975 cells, with an IC50 of 0.77 ± 0.08 and 6.90 ± 0.83 μM, respectively. At concentration of 10 μM, A9 can be employed as the fourth-generation of EGFR inhibitors with the ability to overcome the C797S drug resistance since it can suppress EGFRDel19/T790M/C797S cells and kinase by 98.90% and 85.88%, respectively. Moreover, the tumor-bearing nude mice experiment further shows that A9 can significantly inhibit the growth of tumor in vivo, with the tumor inhibition rate (TIR) of 55.92%, which was equivalent to the positive group. After that, from the result of HE staining experiment and blood biochemical analysis experiment, A9 show low toxicity and good safety, which is worthy of further research and development.PMID:38351876 | DOI:10.1002/cmdc.202300634
Source: ChemMedChem - Category: Chemistry Authors: Source Type: research