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

Abstract

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.

Integrins in the Spotlight of Cancer

“…The most prominent compound targeting integrins might be cilengitide, a cyclic RGD peptide that targets integrins αvβ3 and αvβ5 [214]. We and other groups could show in vitro and in vivo that this peptide inhibits attachment and invasion of different tumor cells [215,216,217,218,219,220,221]. However, cilengitide failed to provide benefit in a clinical trial phase III (CENTRIC study) [222].…”

Implicacions Biol�giques De Les Integrines en C�ncer I Possibles Ter�pies

“…El cilengitide és un pèptid RGD cíclic (cRGD) que inhibeix l'adhesió i la invasió de diferents cèl•lules tumorals. S'ha demostrat que per tal d'obtenir una major eficàcia hi han de ser presents tant la integrina αvβ3 com l'αvβ5 (Christenheit et al, 2016). Tot i que a la fase ii dels assajos clínics va demostrar tenir eficàcia antitumoral i una baixa toxicitat, els resultats de la fase iii no van ser gaire favorables.…”

“…Malgrat el desenvolupament i els estudis duts a terme, cap dels antagonistes descrits s'ha aprovat per a ús clínic en teràpia contra el càncer (taula 5) (Christenheit et al, 2016).…”