title: Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking.
abstract: Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazoline core to selectively inhibit EGFR/HER2 tyrosine kinases. Twelve compounds (8a-8d, 9a, 9c, 9d, 10a, 10c, 11b, 14, and 15) showed nanomolar range of IC50 values on EGFR and/or HER2 kinases. Accordingly, a detailed structure activity relationship (SAR) was established. A molecular docking study demonstrated the favorable binding modes of 8d, 9b, 9d and 10d at the ATP active site of both kinases. A kinase selectivity profile performed for compound 8d showed great selectivity for EGFR and HER2. In addition, 8d, 9c, and 9d exerted selective promising cytotoxic activity over BT-474 cell line with IC50 values of 2.70, 1.82 and 1.95 μM, respectively. From these results, we report analogs 8d, 9c, and 9d as promising candidates for the discovery of well-balanced compounds in terms of the kinase inhibitory potency and antiproliferative activity.
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elkamhawy
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea.
authors.forename: Ahmed Karam
authors.initials: AK
authors.lastname: Farag
authors.affiliation: Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
authors.forename: Ambily Nath Indu
authors.initials: AN
authors.lastname: Viswanath
authors.affiliation: Department of Biomedical Engineering, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Bedair
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, South Korea.
authors.forename: Dong Gyu
authors.initials: DG
authors.lastname: Leem
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, South Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea. Electronic address: r8636@kist.re.kr.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Antiproliferative activity; Bt-474 cell line; EGFR/HER2 dual inhibitors; Kinase panel; Molecular docking; Synthesis