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Eur J Med Chem. 2016 Jul 19;117:283-91. doi: 10.1016/j.ejmech.2016.04.002. Epub 2016 Apr 4.

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

Author information

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.

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

PMID:
27135370
DOI:
10.1016/j.ejmech.2016.04.002
[Indexed for MEDLINE]

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