ADAM proteases: Emerging role and targeting of the non-catalytic domains. (28th December 2019)

• Record Type: Journal Article
• Authors: Saha, Nayanendu; Robev, Dorothea; Himanen, Juha P.; Nikolov, Dimitar B.
• Is Part Of: Cancer letters. Volume 467(2019)
• Page Start: 50
• Page End: 57
• Publication Date: 2019-12-28
• Subjects: ADAM10 -- ADAM17 -- Integrins -- Therapeutic antibody -- Notch signaling; MP Metalloprotease domain -- D Disintegrin domain -- C Cysteine rich domain -- VEGF Vascular endothelial growth factor -- OSCC Oral squamous cell carcinoma -- ScFv Single chain variable fragment -- PDI Protein disulfide isomerase -- TNBC Triple negative breast cancer -- MMP Matrix metalloproteinase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.10.003
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: ADAM proteases are multi domain transmembrane metalloproteases that cleave a range of cell surface proteins and activate signaling pathways implicated in tumor progression, including those mediated by Notch, EFGR, and the Eph receptors. Consequently, they have emerged as key therapeutic targets in the efforts to inhibit tumor initiation and progression. To that end, two main approaches have been taken to develop ADAM antagonists: (i) small molecule inhibitors, and (ii) monoclonal antibodies. In this mini-review we describe the distinct features of ADAM proteases, particularly of ADAM10 and ADAM17, their domain organization, conformational rearrangements, regulation, as well as their emerging importance as therapeutic targets in cancer. Further, we highlight an anti-ADAM10 monoclonal antibody that we have recently developed, which has shown significant promise in inhibiting Notch signaling and deterring growth of solid tumors in pre-clinical settings. Highlights: The multi-domain ADAM proteases shed cell-surface proteins involved in cancer. ADAM proteases have emerged as key therapeutic targets in cancer progression. The substrate-specificity of ADAM proteases is dictated by non-catalytic domains. The non-catalytic domains provide attractive targets for drug development. An anti-ADAM10 antibody to the non-catalytic region deters growth of solid tumors.