Targeting Ligand Cleavage to Inhibit the ErbB Pathway in Cancer

A bstract : ADAMs (a disintegrin and metalloproteases) are zinc‐dependent transmembrane metalloproteases that shed the extracellular domains of membrane‐bound growth factors, cytokines, and receptors. Recently, ADAMs have emerged in ErbB signaling pathways as sheddases or multiple ErbB ligands. As the ErbB pathway is a validated target for anticancer drugs, upstream activators of ErbB ligands, their sheddases, become new drug targets in the ErbB pathway. We have identified selective small molecule inhibitors of ADAM proteases that block shedding and activation of multiple ErbB ligands, and we are planning to test the compounds in the clinic.