Open Access Research Article Article ID: GJCT-2-108

    A Novel Small-Molecule Integrin Antagonist Inhibits Cells Adhesion Followed By Anoikis in Endothelial Cells - A Comparative Analysis with Cilengitide

    Agnieszka Christenheit*, Petra Heffeter and Edgar Selzer

    Background: Despite the crucial role of integrin receptors in cancer pathogenesis and massive efforts towards establishing clinically relevant drugs, to the present no effective integrin antagonist for the treatment of malignant diseases has been introduced into the clinic.

    Context and purpose of the study: The purpose of the study was to examine the cellular effects and molecular mechanisms of a novel anti-integrin compound designated AV-398/38 and to compare it with cilengitide, one of the most advanced and best characterized αVβ3/αVβ5 integrin antagonists. AV-398/38 is a small molecule integrin antagonist that is currently in an early phase of pre-clinical evaluation. It was identified by virtual screening of chemical databases with the aim to detect novel integrin αVβ3 antagonist-like candidates. Based on preliminary in vitro data, the compound was recognized as a potential anti-neoplastic drug candidate, displaying high specificity and binding affinity in the nanomolar range towards the αVβ3 receptor, as well as showing potentially favorable drug-like properties.

    Results: Our studies revealed that its anti-neoplastic properties are most likely mediated by inhibition of integrin-mediated cell attachment to the extracellular matrix resulting in anoikis in a TP53 independent manner. Additionally, we observed inhibition of integrin-linked pathways involved in cell proliferation, survival and migration such as FAK, Akt, and MAPK as well as direct inhibitory effects on cell migration. We compared the effects of the compound with cilengitide, which is one of the bestcharacterized αVβ3 antagonists available.

    Main findings: The main finding was the observation, that AV-398/38 is capable of inducing cell death via induction of anoikis in a TP53 independent manner. 

    Conclusions: Integrin αVβ3/αVβ5 inhibition leads to apoptotic cell death most likely triggered by a loss of adherence. Brief summary and potential implications: Our data indicate that compound AV-398/38 or structurally similar molecules may be promising candidates for preclinical development. 


    Published on: Mar 18, 2016 Pages: 9-18

    Full Text PDF Full Text HTML DOI: 10.17352/gjct.000008
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