Nintedanib-Containing Dual Conjugates Targeting alpha(V)beta(6) Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents

alpha(V)beta(6) Integrin plays a fundamental role in the activation of transforming growth factor-beta (TGF-beta), the major profibrotic mediator; for this reason, alpha(V)beta(6) ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and in vitro biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by c(AmpLRGDL), an alpha(V)beta(6) integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal in vitro antifibrotic properties of the two active units. The integrin ligand portion within the conjugate plays a role in inhibiting profibrotic stimuli, potentiating the nintedanib effect and favoring the selective uptake of the conjugate in cells overexpressing alpha(V)beta(6) integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF.

Automated summary

This study reports the synthesis and in vitro biological evaluation of three new covalent conjugates, consisting of an alpha(V)beta(6) integrin-recognizing small cyclopeptide and nintedanib, for the treatment of fibrotic diseases. One of these conjugates demonstrates optimal antifibrotic properties in vitro. The integrin ligand within the conjugate plays a role in inhibiting fibrotic stimuli and enhancing the effect of nintedanib, while selectively targeting cells overexpressing alpha(V)beta(6) integrin.