Discovery of novel 2,4-diarylaminopyrimidine derivatives as potent and selective epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M resistance mutation
- Eur J Med Chem. 2018 May 25:152:298-306. doi: 10.1016/j.ejmech.2018.04.052.
- 1. School of Pharmacy, Fudan University, Shanghai, 201203, China.
- 2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
- 3. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- 4. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- 5. School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
- 6. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
- 7. School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
A series of novel 2,4-diarylaminopyrimidine derivatives of AZD9291 were discovered as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. The majority of these compounds exhibited moderate to excellent EGFR T790 M/L858R inhibitory activities and comparable anti-proliferative activities against double mutant over-expressed NCI-H1975 cells to that of AZD9291. The most promising compounds 8a displayed an IC50 of 4.1 nM against EGFR L858R/T790M mutants. 8a also showed excellent cytotoxic effect against NCI-H1975 cells with an IC50 of 59 nM and 100-fold selectivity over wide-type EGFR over-expressed A431 cells. Compound 8a significantly inhibited tumor growth in NCI-H1975 xenograft models at a non-toxic dose. Docking study performed for 8a with ATP binding site of EGFR-TK showed the similar binding mode to that of AZD9291. All these results suggested that compound 8a was a potential mutant-selective EGFR Inhibitor.