Av integrins (avb1, avb3, avb5, avb6, avb8) 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 b (TGF-b). Members of this class of integrins have been the target of therapeutic intervention due to recent evidence implicating av integrin activation/upregulation as a key mediator of organ specific fibrotic disease in humans. Specifically, avb6 and avb1 have been implicated in Idiopathic Pulmonary Fibrosis (IPF) and Primary Sclerosing Cholangitis (PSC) while avb1 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 av integrin inhibitors for the treatment of fibrosis

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.