Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 16; p. 127327
• Main Authors: Su, Zhicheng, Yang, Tingyuan, Wang, Jie, Lai, Mengzhen, Tong, Linjiang, Wumaier, Gulinuer, Chen, Zhuo, Li, Shengqing, Li, Honglin, Xie, Hua, Zhao, Zhenjiang
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2020; Elsevier
• Subjects: C797S; Chemistry; Chemistry, Medicinal; Chemistry, Organic; EGFR; Life Sciences & Biomedicine; NSCLC; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; NSCLC; EGFR; C797S; CELL LUNG-CANCER; MUTANT; GEFITINIB; C797S MUTATION; ACQUIRED-RESISTANCE; DISCOVERY; AZD9291
• DOI: 10.1016/j.bmcl.2020.127327
• ISSN: 0960-894X

[Display omitted] 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.