title: Novel 4-anilinoquinazoline derivatives featuring an 1-adamantyl moiety as potent EGFR inhibitors with enhanced activity against NSCLC cell lines.
abstract: With the aim of overcoming gefitinib resistance, a series of novel quinazoline derivatives bearing an adamantyl group on the aniline ring were synthesized as potent epidermal growth factor receptor (EGFR) inhibitors. Most of these analogues are comparable to gefitinib in their ability to inhibit non-small cell lung cancer (NSCLC) cell lines, and several also exhibited significantly enhanced anti-tumor potency. Specifically, compound 3d, with an IC50 value of 2.06 μM against A431 cells with the wild-type EGFR and of 0.009 μM against the gefitinib-sensitive cells, displayed approximately 5-fold higher potency than the lead compound to inhibit the cells harboring the EGFR(T790M) mutant. In addition, the molecular simulation and Western blot analysis results also indicated that these compounds effectively interfered with the EGFR(T790M) activity, and may serve as a new alternative structure to develop more effective antitumor agents.
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Yu
authors.affiliation: Respiratory Department, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ge
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Song
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jin
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: kexinliu@dlmedu.edu.cn.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada. Electronic address: youwen.zhou@ubc.ca.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D017354:Point Mutation; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Adamantyl; EGFR; NSCLC; Quinazoline; T790M