αvβ6, a member of the arginyl glycyl aspartate (RGD) subfamily, is a heterodimer of αv and β6 integrin subunit. Specifically, αvβ6 is an epigenetic integrin. αvβ6 is not expressed in epithelial cells of healthy adults but is up-regulated in wound healing and cancer. αvβ6 is the receptor of extracellular matrix (ECM) proteins, including fibronectin, latent associated peptide (LAP). αvβ6 binds to LAP and releases TGF through cytoskeletal force-β1. Besides, integrins bind to specific extracellular proteins in ECM or other cells and then transduce signals in cells to influence cell behavior. Its main function is to activate the cytokine TGF-β1. TGF-β/Smad signaling pathway regulates many processes, including cell proliferation, differentiation, angiogenesis, epithelial-mesenchymal transition (EMT), and immunosuppression.

Furthermore, αvβ6 is a target in idiopathic pulmonary fibrosis (IPF), other types of organ fibrosis, and cancer. EMD527040 (HY-101473) is a highly selective αvβ6 antagonist with anti-fibrotic activities. Interestingly, EMD527040 can also be used for carcinoma and liver fibrosis-related research.

EMD527040 selectively inhibits binding of recombinant αvβ6 to fibronectin (IC₅₀: 6 nM) with weak affinity for αvβ3 and αvβ5. Importantly, EMD527040 inhibits the attachment of αvβ6 expressing cells (UCLAP3 cells) to fibronectin (IC₅₀: 1.6 μM). Besides, EMD527040 (20-60 mg/kg, i.p.) attenuates bile ductular proliferation and peribiliary collagen deposition by 40-50%. Obviously, EMD527040 downregulates of fibrogenic genes and upregulates fibrinolytic genes.

In conclusion, EMD527040 is a highly selective αvβ6 antagonist with antifibrotic activities.