SMARTer design of a novel structure‐based ADAM8 inhibitor to combat pancreatic cancer

Abstract

Members of the ADAMs (A Disintegrin And Metalloprotease) family are involved in cell migration, invasion and growth factor signaling, all key processes in cancer. Pancreatic ductal adenocarcinoma (PDAC), marked by massive infiltration of tumor cells into the pancreas and metastasis into liver and lungs, has the highest mortality rate of all solid organ cancers. In PDAC, high ADAM8 levels correlate with decreased survival. In cell membranes, ADAM8 associates with itself to allow autocatalytic activation. ADAM8 then binds to β1‐integrin, a transmembrane receptor that attaches cells to the extracellular matrix (ECM) and allows communication across the membrane. Both interactions cause ECM remodeling via intracellular signaling pathways by phosphorylation of β1‐associated kinases focal adhesion kinase and extracellular signal‐regulated kinase which in turn activate the release of matrix‐metalloproteinases, potent mediators of ECM degradation. The Governor's Academy SMART (Students Modeling A Research Topic) team designed a model using 3D printing technology to highlight structural features, providing functional insight into the mechanism by which ADAM8 causes tumor progression in PDAC. Since its protein‐protein interactions are crucial for its function in tumors, blocking ADAM8 to limit invasive tumor growth is a promising therapeutic strategy. Supported by a grant from NIH‐SEPA 1R25OD010505–01