7OVY

Crystal structure of a dimeric based inhibitor JG34 in complex with the MMP-12 catalytic domain

Summary for 7OVY

• Entry DOI: 10.2210/pdb7ovy/pdb
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: hydrolase, hydrolase-inhibitor crystal complex, hydrolase inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 19407.69

Authors

Ciccone, L.,Rossello, A.,Vera, L.,Nuti, E.,Stura, E.A. (deposition date: 2021-06-15, release date: 2021-10-27, Last modification date: 2024-01-31)

Primary citation

Cuffaro, D.,Camodeca, C.,Tuccinardi, T.,Ciccone, L.,Bartsch, J.W.,Kellermann, T.,Cook, L.,Nuti, E.,Rossello, A.
Discovery of Dimeric Arylsulfonamides as Potent ADAM8 Inhibitors.
Acs Med.Chem.Lett., 12:1787-1793, 2021

PubMed Abstract: The metalloproteinase ADAM8 is upregulated in several cancers but has a dispensable function under physiological conditions. In tumor cells, ADAM8 is involved in invasion, migration, and angiogenesis. The use of bivalent inhibitors could impair migration and invasion through the double binding to a homodimeric form of ADAM8 located on the cell surface of tumor cells. Herein we report the rational design and synthesis of the first dimeric ADAM8 inhibitors selective over ADAM10 and matrix metalloproteinases. Bivalent derivatives have been obtained by dimerizing the structure of a previously described ADAM17 inhibitor, JG26. In particular, derivative was shown to inhibit ADAM8 proteolytic activity and in cell-based assays at nanomolar concentration. Moreover, it was more effective than the parent monomeric compound in blocking invasiveness in the breast cancer MDA-MB-231 cell line, thus supporting our hypothesis about the importance of inhibiting the active homodimer of ADAM8.

PubMed: 35111280
DOI: 10.1021/acsmedchemlett.1c00411

Experimental method

X-RAY DIFFRACTION (1.24 Å)