2. Academic Validation
  3. Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate

Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate

  • Eur J Med Chem. 2016 Jul 19:117:283-91. doi: 10.1016/j.ejmech.2016.04.002.
Andrea Tarozzi 1,  Chiara Marchetti 2,  Benedetta Nicolini 1,  Massimo D'Amico 1,  Nicole Ticchi 3,  Letizia Pruccoli 1,  Vincenzo Tumiatti 1,  Elena Simoni 2,  Alessio Lodola 4,  Marco Mor 4,  Andrea Milelli 5,  Anna Minarini 6
Affiliations

Affiliations

  • 1 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
  • 3 Interdepartmental Center for Industrial Research, Advanced Mechanical and Materials, Alma Mater Studiorum-University of Bologna, 47923 Rimini, Italy.
  • 4 Pharmacy Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
  • 5 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy. Electronic address: andrea.milelli3@unibo.it.
  • 6 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy. Electronic address: anna.minarini@unibo.it.
PMID: 27135370 DOI: 10.1016/j.ejmech.2016.04.002
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.

Keywords

Akt phosphorylation; EGFR-TK inhibitors; Isothiocyanate; Multitarget agents; Sulforaphane.

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