Modification of osimertinib to discover new potent EGFRC797S-TK inhibitors.
Eur J Med Chem
; 261: 115865, 2023 Dec 05.
Article
in En
| MEDLINE
| ID: mdl-37839342
ABSTRACT
The EGFRC797S mutation is a dominant mechanism of acquired resistance after the treatment of non-small cell lung cancer (NSCLC) with osimertinib in clinic. To date, there is no inhibitor approved to overcome the resistance caused by osimertinib. In this study, a series of compounds with phenylamino-pyrimidine scaffold deriving from osimertinib were designed, synthesized and evaluated as fourth-generation EGFRC797S-TK inhibitors. Consequently, compound Os30 exhibited potent inhibitory activities against both EGFRDel19/T790M/C797S TK and EGFRL858R/T790M/C797S TK with IC50 values of 18 nM and 113 nM, respectively. Moreover, Os30 can powerfully inhibit the proliferation of KC-0116 (BaF3-EGFRDel19/T790M/C797S) and KC-0122 (BaF3-EGFRL858R/T790M/C797S) cells. In addition, Os30 can suppress EGFR phosphorylation in a concentration-dependent manner in KC-0116 cells, arrest KC-0116 cells at G1 phase and induce the apoptosis of KC-0116 cells. More importantly, Os30 showed potent antitumor efficacy in the KC-0116 cells xenograft nude mice tumor model with the tumor growth inhibitory rate of 77.6% at a dosage of 40 mg/kg. These findings demonstrate that modification of osimertinib can discover new potent EGFRC797S-TK inhibitors, and compound Os30 is a potent fourth-generation EGFR inhibitor to treat NSCLC with EGFmRC797S mutation.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma, Non-Small-Cell Lung
/
Lung Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2023
Document type:
Article