title: Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate.
abstract: Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targets the PI3K-Akt pathway whose dysregulation is implicated in many functions of cancer cells. According to these considerations, a series of multitarget molecules have been designed by combining key structural features derived from an EGFR-TKI, PD168393, and the isothiocyanate sulforaphane. Among the obtained molecules 1-6, compound 6 emerges as a promising lead compound able to exert antiproliferative and proapoptotic effects in A431 epithelial cancer cell line by covalently binding to EGFR-TK, and reducing the phosphorylation of Akt without affecting the total Akt levels.
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tarozzi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nicolini
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Interdepartmental Center for Industrial Research, Advanced Mechanical and Materials, Alma Mater Studiorum-University of Bologna, 47923 Rimini, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ticchi
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Pruccoli
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Simoni
authors.affiliation: Pharmacy Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.affiliation: Pharmacy Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy. Electronic address: andrea.milelli3@unibo.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy. Electronic address: anna.minarini@unibo.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D013454:Sulfoxides
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D017879:Isothiocyanates; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D013454:Sulfoxides; C016766:sulforaphane
keywords: Akt phosphorylation; EGFR-TK inhibitors; Isothiocyanate; Multitarget agents; Sulforaphane