7OVY

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

7OVY の概要

• エントリーDOI: 10.2210/pdb7ovy/pdb
• 分子名称: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (7 entities in total)
• 機能のキーワード: hydrolase, hydrolase-inhibitor crystal complex, hydrolase inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19407.69

構造登録者

Ciccone, L.,Rossello, A.,Vera, L.,Nuti, E.,Stura, E.A. (登録日: 2021-06-15, 公開日: 2021-10-27, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.24 Å)