Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.
The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR19D/T790M/C797S mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR19D/T790M/C797S (IC50 = 15.3 nM) and good selectivity over EGFR WT (IC50 > 1000 nM), L858R/T790M (IC50, 156.6 nM) and L858R/T790M/C797S (IC50, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR19D/T790M/C797S cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR19D/T790M/C797S inhibitors.
['Su|Zhicheng|Z|', 'Yang|Tingyuan|T|', 'Wang|Jie|J|', 'Lai|Mengzhen|M|', 'Tong|Linjiang|L|', 'Wumaier|Gulinuer|G|', 'Chen|Zhuo|Z|', 'Li|Shengqing|S|', 'Li|Honglin|H|', 'Xie|Hua|H|', 'Zhao|Zhenjiang|Z|']
D000970:Antineoplastic Agents D017209:Apoptosis D059447:Cell Cycle Checkpoints D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D004305:Dose-Response Relationship, Drug D015195:Drug Design D004354:Drug Screening Assays, Antitumor D066246:ErbB Receptors D006801:Humans D062105:Molecular Docking Simulation D015394:Molecular Structure D009154:Mutation D047428:Protein Kinase Inhibitors D013329:Structure-Activity Relationship
EGFR C797S NSCLC