Synthesis of Dual-Action Ligands Targeting Both Integrin αVβ3 and VEGF Receptors

Some specific cell surface receptors, such as integrins αVβ3, αVβ5 and α5β1 and the growth factor receptors VEGFRs, play a key role in the regulation of tumor angiogenesis, progression and metastasis through the formation of specific protein-protein complexes (“cross-talk”).1 The VEGFR-2/αVβ3 association has been provided in vivo;2 moreover, a dual-specific engineered protein, able to bind both VEGFR-2 and integrin αVβ3, showed a potent biological activity by blocking angiogenic processes in vitro and in vivo.3
Aiming at inhibiting both αVβ3 and VEGFR-1 receptors, the dual-specific agents 1 and 2 (FIG. 1), were synthesized conjugating the selective αVβ3/αVβ5 integrin ligand c[DKP-f3-RGD]4 and the VEGFR-1 ligand MA,5 via a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The biological and conformational properties of the two conjugates are under investigation.