Ectodomain shedding of extracellular and membrane proteins is of fundamental importance for cell-cell communication in neoplasias. A Disintegrin And Metalloproteinase (ADAM) proteases constitute a family of multifunctional, membrane-bound proteins with traditional sheddase functions. Their protumorigenic potential has been attributed to both, essential (ADAM10 and ADAM17) and 'dispensable' ADAM proteases (ADAM8, 9, 12, 15, and 19). ADAM8 that has been identified as a significant player in aggressive malignancies including breast, pancreatic, and brain cancer. High expression levels of ADAM8 are associated with invasiveness and predict a poor patient outcome, indicating a prognostic and diagnostic potential of ADAM8. Current knowledge of substrates and interaction partners gave rise to the hypothesis that ADAM8 dysregulation affects diverse processes in tumor biology, attributable to different functional cores of the multidomain enzyme. Proteolytic degradation of extracellular matrix (ECM) components, cleavage of cell surface proteins, and subsequent release of soluble ectodomains promote cancer progression via induction of angiogenesis and metastasis. Moreover, there is increasing evidence for significance of a non-proteolytic function of ADAM8. With the disintegrin (DIS) domain ADAM8 binds integrins such as β1 integrin, thereby activating integrin signaling pathways. Thus, ADAM8 protease has been recently proposed as a possible target for drug design against metastatic complications of some tumors. Dimeric Arylsulfonamides have been proved as potent inhibitors of ADAM8 enzymatic activity. Here you can see a recent crystal structure of the human ADAM8 enzyme in complex with a complex benzene-1,3-dicarboxamide inhibitor (PDB code: 7OVY)
#molecularart ... #immolecular ... #ADAM8 ... #protease .... #cancer .... #metastasis ... #sulfonamide ... #inhibitor ... #drugdesign .... #xray
Rendered with @proteinimaging and finished with @corelphotopaint
#molecularart ... #immolecular ... #ADAM8 ... #protease .... #cancer .... #metastasis ... #sulfonamide ... #inhibitor ... #drugdesign .... #xray
Rendered with @proteinimaging and finished with @corelphotopaint
