The αv integrins (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8) are a subset of a family of heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix signaling. This subset binds to a conserved RGD sequence motif found in endogenous ligands leading to activation of the latent pro-fibrotic cytokine Transforming Growth Factor β (TGF-β). Members of this class of integrins have been the target of therapeutic intervention due to recent evidence implicating αv integrin activation/upregulation as a key mediator of organ specific fibrotic disease in humans. Specifically, αvβ6, and αvβ1 have been implicated in Idiopathic Pulmonary Fibrosis (IPF) and Primary Sclerosing Cholangitis (PSC) while αvβ1 is upregulated in parenchymal liver fibrosis associated with non-alcoholic steatohepatitis (NASH). In this talk, we will describe our integrin inhibitor library, disclose structures of integrin selective compounds, show in vivo efficacy in preclinical models of fibrotic disease as well as in precision-cut tissue slices from explanted human tissue and describe data on modulation of human profibrotic genes.

Discovery of αv integrin inhibitors for the treatment of fibrosis

ACS Spring Meeting 2021

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