Integrin αvβ6 is a member of the arginyl glycyl aspartate (RGD) subfamily of heterodimer transmembrane glycoprotein receptor 9. Specifically, αvβ6 is an epigenetic integrin. It is the receptor of extracellular matrix (ECM) proteins fibronectin, fibronectin, technogenic and TGF-βlatent associated peptide (LAP). Besides, integrins bind to specific extracellular proteins in the extracellular matrix or other cells and then transduce signals in cells to influence cell behavior. Its main function is to activate the cytokine TGF-b1- β1. Moreover, αvβ6 binds to lap and releases TGF through cytoskeletal force-β1. TGF-β1 regulates many processes, including cell proliferation, differentiation, angiogenesis, epithelial-mesenchymal transition (EMT), and immunosuppression.
Furthermore, Integrin αvβ6 was not expressed in epithelial cells of healthy adults but was up-regulated in wound healing and cancer. Meanwhile, αvβ6 can regulate invasion, inhibit apoptosis, regulate the expression of matrix metalloproteinase (MMP) and activate TGF-β1. Nonetheless, αvβ6 mediates the binding of cells to fibronectin, so it can become a major adhesion receptor. αvβ6 is a target in idiopathic pulmonary fibrosis (IPF), other types of organ fibrosis, and cancer. Today, we will introduce a highly selective αvβ6 antagonist, EMD527040.
EMD527040 is a Highly Selective αvβ6 Antagonist with Antifibrotic Activities.
First of all, EMD527040 is a highly selective αvβ6 antagonist with antifibrotic activities. Interestingly, EMD527040 can be used for carcinoma and liver fibrosis research.
In the second place, EMD527040 inhibits binding of recombinant αvβ6 to fibronectin at 6 nM as compared to >9.5 μM for αvβ3 and αvβ5 integrins (IC5050). Importantly, EMD527040 inhibits the attachment of αvβ6 expressing cells (UCLAP3 cells) to fibronectin at IC50 of 1.6 μM. Particularly, EMD527040 has IC50s>50 μM for αvβ3 and αvβ5 integrins.
Last but not the least, EMD527040 with 20-60 mg/kg by ip attenuates bile ductular proliferation and peribiliary collagen deposition by 40-50%. Obviously, EMD527040 induces downregulation of fibrogenic and upregulation of fibrinolytic genes. EMD527040 improves liver architecture and function. Additionally, EMD527040 significantly reduced liver and spleen weights by 22% and 50%, respectively in Mdr2(Abcb4)-/- mice
All in all, EMD527040 is a highly selective αvβ6 antagonist with antifibrotic activities.
Eleonora Patsenker, et al. Gastroenterology. 2008 Aug;135(2):660-70.