Abstract
We previously reported the anti-migratory function of 3-aryl-2-quinolone derivatives, chemically close to flavonoids (Joseph et al., 2002). Herein we show that 3-arylquinoline or 3-aryl-2-quinolone derivatives disrupt cell adhesion in a dose dependent and reversible manner yet antagonized by artificial integrin activation such as manganese. Relying on this anti-adhesive activity, a Structure-Activity Relationship (SAR) study was established on 20 different compounds to throw the bases of future optimization strategies. Active drugs efficiently inhibit platelet spreading, aggregation, and clot retraction, processes that rely on αllbβ3 integrin activation and clustering. In vitro these derivatives interfere with β3 cytoplasmic tail interaction with kindlin-2 in pulldown assays albeit little effect was observed with pure proteins suggesting that the drugs may block an alternative integrin activation process that may not be directly related to kindlin recruitment. Ex vivo, these drugs blunt integrin signaling assayed using focal adhesion kinase auto-phosphorylation as a read-out. Hence, 3-arylquinoline and 3-aryl-2-quinolone series are a novel class of integrin activation and signaling antagonists.
Highlights
Many physiological and pathological processes are largely dependent on cell adhesion to the surrounding extracellular matrix (ECM) [1]
The main cell adhesion receptors, are transmembrane, heterodimeric proteins composed of a large extracellular domain that interacts with specific ECM proteins and a short cytoplasmic tail which recruits a complex and dynamic platform of proteins involved in both signaling and mechanical functions
We studied BJINT006 and BJINT020 adhesion inhibition on cells spread on fibronectin and compared it to cells attached to poly-lysine, a substrate known to support cell adhesion in a non-specific, integrin-independent manner [32]
Summary
Many physiological and pathological processes are largely dependent on cell adhesion to the surrounding extracellular matrix (ECM) [1]. Most of integrin targeting compounds, including antagonist monoclonal antibodies, peptide derivatives and small molecule inhibitors, were designed on a ligand-based strategy They mimic all or part of the binding domain of integrin substrates, often recognized through their RGD motif. Such molecules act as competitors and efficiently prevent integrin mediated cell attachment or platelet aggregation. Though, they act as partial agonists of integrin signaling [11], leading to significant side effects that have, so far, reduced the use of the related therapeutic strategies [12,13,14]. Treatments with integrin antagonists often result in modification of the integrin expression pattern and drug resistance, putting forward the need of inhibitors with multiple targets [15]
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