title: Identification of novel 4-anilinoquinazoline derivatives as potent  EGFR inhibitors both under normoxia and hypoxia.
abstract: A novel series of 4-anilinoquinazoline derivatives (19a-19t) were designed and synthesized through incorporation of the 2-nitroimidazole moiety into the 4-anilinoquinazoline scaffold of EGFR inhibitors. The most promising compound 19h displayed potent EGFR inhibitory activity with the IC50 value of 0.47 nM. It also strongly suppressed the proliferation of A549 and HT-29 cells with sub-micromolar IC50 values both under normoxia and hypoxia, which were several folds more potent than gefitinib and erlotinib. Further reductive mimic investigation revealed that 19h could be reductive activated under hypoxia and was fully consistent with the results of cell apoptotic assay and in vitro metabolism evaluation. Our results suggest that the incorporation of hypoxia-activated moiety into EGFR inhibitor scaffold might be a tractable strategy to overcome the tumor hypoxia.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Cheng
authors.forename: Youting
authors.initials: Y
authors.lastname: Yuan
authors.forename: Ni
authors.initials: N
authors.lastname: Qiu
authors.forename: Peng
authors.initials: P
authors.lastname: Peng
authors.forename: Rong
authors.initials: R
authors.lastname: Sheng
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D019073:HT29 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D009249:NADP / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000599916:N-(3-ethynylphenyl)-6-methoxy-7-((5-(2-nitro-1H-imidazol-1-yl)pentyl)oxy)quinazolin-4-amine; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D009249:NADP; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib; C023650:aniline