Synthesis and Evaluation of 2-Amine-4-oxyphosaniline Pyrimidine Derivatives as EGFR L858R/T790M/C797S Mutant Inhibitors
-
- Zhang Mingguang
- Jiangsu Vocational College of Medicine
-
- Yang Yang
- Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd.
-
- Wang Yunyun
- School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University
-
- Wang Jia
- Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd.
-
- Wu Hongyan
- Jiangsu Vocational College of Medicine
-
- Zhu Yongqiang
- Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd. College of Life Science, Nanjing Normal University
この論文をさがす
抄録
<p>Epidermal growth factor receptor (EGFR) C797S mutation leads to Osimertinib drug resistance by disturbing the covalent biding of Michael acceptor group to the Cys797 residue in the ATP biding cleft. In this manuscript, a class of 2-amine-4-oxyphosaniline pyrimidine derivatives were designed, synthesized and evaluated as new noncovalent reversible EGFR inhibitors against L858R/T790M/C797S (CTL) triple mutant. The kinases inhibitiory activity evaluation showed that four compounds exhibited significant inhibitory activities against CTL (IC50 < 30 nM). In particularly, the most promising compound 7a showed excellent enzymatic inhibitory activity against CTL with IC50 value of 9.9 nM, which was more potent than control compound Osimertinib. Moreover, cell proliferation assays indicated that 7a effectively inhibited H1975-EGFR L858R/T790M/C797S with IC50 value of 0.33 µM. Furthermore, compound 7a displayed good metabolic stabilities in human, rat and mouse liver microsomes, and the putative biding mode of compound 7a with ATP was revealed by molecular docking study. These findings strongly indicated that compound 7a was a promising L858R/T790M/C797S mutant EGFR inhibitor.</p>
収録刊行物
-
- CHEMICAL & PHARMACEUTICAL BULLETIN
-
CHEMICAL & PHARMACEUTICAL BULLETIN 71 (2), 140-147, 2023-02-01
公益社団法人 日本薬学会