title: 6-Aryl and heterocycle quinazoline derivatives as potent EGFR inhibitors with improved activity toward gefitinib-sensitive and -resistant tumor cell lines.
abstract: A group of novel anilinoquinazoline derivatives with variable aryl and heterocyclic substituents at position 6 were synthesized and tested for their EGFR-inhibitory activity. Aryl and heterocyclic rings were attached to the quinazoline scaffold through different linkages such as imine, amide, and thiourea. Most of the aryl and heterocyclic derivatives showed potent inhibition of wild-type EGFR with IC₅₀ values in the low nanomolar range. Among these, thiourea derivatives 6 a, 6 b and compound 10 b also retained significant activity toward the gefitinib-insensitive EGFR(T790M/L858R) mutant, displaying up to 24-fold greater potency than gefitinib. In addition, cell growth inhibitory activity was tested against cancer cell lines with wild-type (KB cells) and mutant EGFR (H1975 cells). Several compounds including 6 a were found to be more potent than the reference compound gefitinib toward both cell lines, as was the case for compound 10 b against H1975 cells. Therefore, compounds 6 a and 10 b in particular may serve as new leads for the development of inhibitors effective against wild-type EGFR as well as gefitinib-resistant mutants.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Helmholtz Institute for Pharmaceutical Research Saarland-HIPS, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Hamed
authors.forename: Dalal A
authors.initials: DA
authors.lastname: Abou El Ella
authors.forename: Adam B
authors.initials: AB
authors.lastname: Keeton
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR; antitumor agents; heterocycles; quinazoline; tumor resistance