title: Design and Synthesis of 4-Anilinothieno[2,3-d]pyrimidine-Based Compounds as Dual EGFR/HER-2 Inhibitors.
abstract: Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e-g) demonstrated low to submicromolar inhibition of both kinases with IC50values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50EGFR/HER-2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Egyptian Russian University, Badr City, Cairo, Egypt.
authors.forename: Soha R
authors.initials: SR
authors.lastname: Abd El Hadi
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ain Shams University, Cairo, Egypt.
authors.forename: Deena S
authors.initials: DS
authors.lastname: Lasheen
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Egyptian Russian University, Badr City, Cairo, Egypt.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Hassan
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ain Shams University, Cairo, Egypt. khaled.abouzid@pharma.asu.edu.eg.
authors.forename: Khaled A M
authors.initials: KA
authors.lastname: Abouzid
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D062105:Molecular Docking Simulation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Antiproliferative activity; Docking study; EGFR/HER2 kinase; Thienopyrimidine