Targeting α4β1 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 α 4 β 1 , are considered important therapeutic targets. In this study, a series of novel compounds were synthesized and evaluated for affinity and potency towards α 4 β 1 , and selectivity towards α 5 β 1 , and α M β 2 integrins. Three compounds 3 , 4 , and 8 showed excellent binding affinities (K i < 10 nM) for α 4 β 1 . In cell adhesion assays these three ligands behaved as antagonists of α 4 β 1 , 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 α 4 β 1 (IC 50 15 ± 3 nM) and an agonist against α M β 2 integrin (EC 50 23 ± 5 nM). Compound 2 , a fluorinated β-lactam derivative, was a selective and potent agonist of α 5 β 1 (EC 50 45.98 ± 7.92 nM). Compound 5 , although it seems to bind to a different site compared to LDV in α 4 β 1 integrin, showed an agonist behaviour in cell adhesion mediated by α 4 β 1 and α 5 β 1 integrin (EC 50 25 ± 3 and 4.8 ± 3.4 nM, respectively) and in activating α 4 β 1 integrin-mediated ERK1/2 and Akt phosphorylation. Compound 8 was the most potent agonist of the series against α M β 2 (EC 50 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.