Targeting αβ integrin: from cyclic to linear ligands, effects of chemical modifications.

The immune system depends on integrins for adhesion and migration during leukocyte trafficking and for intracellular signalling. There is a causal relationship between dysregulation of integrin expression and the onset of pathological conditions, such as autoimmune diseases, inflammation, cancer, and infections. Therefore, integrins, such as αβ, are considered important therapeutic targets. In this study, a series of novel compounds were synthesized and evaluated for affinity and potency towards αβ, and selectivity towards αβ, and αβ integrins. Three compounds 3, 4, and 8 showed excellent binding affinities (K < 10 nM) for αβ. In cell adhesion assays these three ligands behaved as antagonists of αβ, as confirmed by integrin-mediated intracellular signalling with a functional selectivity over ERK1/2 signalling pathway. Notably, compound 4, a proline derivative, was an antagonist against αβ (IC 15 ± 3 nM) and an agonist against αβ integrin (EC 23 ± 5 nM). Compound 2, a fluorinated β-lactam derivative, was a selective and potent agonist of αβ (EC 45.98 ± 7.92 nM). Compound 5, although it seems to bind to a different site compared to LDV in αβ integrin, showed an agonist behaviour in cell adhesion mediated by αβ and αβ integrin (EC 25 ± 3 and 4.8 ± 3.4 nM, respectively) and in activating αβ integrin-mediated ERK1/2 and Akt phosphorylation. Compound 8 was the most potent agonist of the series against αβ (EC 1.4 ± 0.2 nM). Overall, the present study provides new insights into the effects of new integrin ligands that could be considered as potential lead compounds for therapeutic applications in inflammatory diseases and cancer.