Targeting the Hemopexin-like Domain of Latent Matrix Metalloproteinase-9 (proMMP-9) with a Small Molecule Inhibitor Prevents the Formation of Focal Adhesion Junctions
Autor: | Michael Tong, Markus A. Seeliger, Anushree Kamath, Nicole S. Sampson, Kunal Kumar, Jian Cao, Iwao Ojima, Monaf Awwa, Vincent M. Alford, Xiaodong Ren, Qianwen Gan |
---|---|
Rok vydání: | 2017 |
Předmět: |
Models
Molecular 0301 basic medicine Matrix metalloproteinase inhibitor Integrin alpha4beta1 Matrix Metalloproteinase Inhibitors Matrix metalloproteinase Biochemistry Small Molecule Libraries Focal adhesion 03 medical and health sciences 0302 clinical medicine Protein Domains Cell Movement Hemopexin Cell Line Tumor Neoplasms Chlorocebus aethiops Animals Humans Paxillin Enzyme Precursors Focal Adhesions biology Chemistry CD44 Cell migration General Medicine Molecular biology Cell biology Hyaluronan Receptors 030104 developmental biology Matrix Metalloproteinase 9 030220 oncology & carcinogenesis COS Cells biology.protein Molecular Medicine Chickens Proto-oncogene tyrosine-protein kinase Src |
Zdroj: | ACS Chemical Biology. 12:2788-2803 |
ISSN: | 1554-8937 1554-8929 |
Popis: | A lack of target specificity has greatly hindered the success of inhibitor development against matrix metalloproteinases (MMPs) for the treatment of various cancers. The MMP catalytic domains are highly conserved, whereas the hemopexin-like domains of MMPs are unique to each family member. The hemopexin-like domain of MMP-9 enhances cancer cell migration through self-interaction and heterointeractions with cell surface proteins including CD44 and α4β1 integrin. These interactions activate EGFR-MAP kinase dependent signaling that leads to cell migration. In this work, we generated a library of compounds, based on hit molecule N-[4-(difluoromethoxy)phenyl]-2-[(4-oxo-6-propyl-1H-pyrimidin-2-yl)sulfanyl]-acetamide, that target the hemopexin-like domain of MMP-9. We identify N-(4-fluorophenyl)-4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-ylthio)butanamide, 3c, as a potent lead (Kd = 320 nM) that is specific for binding to the proMMP-9 hemopexin-like domain. We demonstrate that 3c disruption of MMP-9 homodimerization prevents association of proMMP-9 with both α4β1 integrin and CD44 and results in the dissociation of EGFR. This disruption results in decreased phosphorylation of Src and its downstream target proteins focal adhesion kinase (FAK) and paxillin (PAX), which are implicated in promoting tumor cell growth, migration, and invasion. Using a chicken chorioallantoic membrane in vivo assay, we demonstrate that 500 nM 3c blocks cancer cell invasion of the basement membrane and reduces angiogenesis. In conclusion, we present a mechanism of action for 3c whereby targeting the hemopexin domain results in decreased cancer cell migration through simultaneous disruption of α4β1 integrin and EGFR signaling pathways, thereby preventing signaling bypass. Targeting through the hemopexin-like domain is a powerful approach to antimetastatic drug development. |
Databáze: | OpenAIRE |
Externí odkaz: |