Nintedanib-Containing Dual Conjugates Targeting αβ Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents.

αβ Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, αβ ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by (AmpLRGDL), an αβ integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal 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 αβ integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF.