Nintedanib-Containing Dual Conjugates Targeting αVβ6 Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents

Kelly Bugatti; Elena Andreucci; Noemi Monaco; Lucia Battistini; Silvia Peppicelli; Jessica Ruzzolini; Claudio Curti; Franca Zanardi; Francesca Bianchini; Andrea Sartori

doi:10.1021/acsomega.2c00535

Nintedanib-Containing Dual Conjugates Targeting α_Vβ₆ Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents

ACS Omega. 2022 May 17;7(21):17658-17669. doi: 10.1021/acsomega.2c00535. eCollection 2022 May 31.

Affiliations

¹ Department of Food and Drug, University of Parma, Parco Area delle Scienze 27A, 43124 Parma, Italy.
² Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy.

Abstract

α_Vβ₆ Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, α_Vβ₆ 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 α_Vβ₆ 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 α_Vβ₆ integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF.