Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cancer Res. 2011 Jul 15;71(14):4977-88. doi: 10.1158/0008-5472.CAN-10-4552. Epub 2011 Jun 6.

Small-molecule anticancer compounds selectively target the hemopexin domain of matrix metalloproteinase-9.

Author information

  • 1Departments of Medicine, Chemistry, Molecular and Cellular Biology, and Applied Mathematics, and Bioinformatics Facility, Stony Brook University, Stony Brook, NY 11794, USA.

Erratum in

  • Cancer Res. 2012 Oct 1;72(19):5141-2. Dosage error in article text.

Abstract

Lack of target specificity by existing matrix metalloproteinase (MMP) inhibitors has hindered antimetastatic cancer drug discovery. Inhibitors that bind to noncatalytic sites of MMPs and disrupt protease signaling function have the potential to be more specific and selective. In this work, compounds that target the hemopexin (PEX) domain of MMP-9 were identified using an in silico docking approach and evaluated using biochemical and biological approaches. Two of the selected compounds interfere with MMP-9-mediated cancer cell migration and proliferation in cells expressing exogenous or endogenous MMP-9. Furthermore, these inhibitors do not modulate MMP-9 catalytic activity. The lead compound, N-[4-(difluoromethoxy)phenyl]-2-[(4-oxo-6-propyl-1H-pyrimidin-2-yl)sulfanyl]-acetamide, specifically binds to the PEX domain of MMP-9, but not other MMPs. This interaction between the compound and the PEX domain results in the abrogation of MMP-9 homodimerization and leads to blockage of a downstream signaling pathway required for MMP-9-mediated cell migration. In a tumor xenograft model, this pyrimidinone retarded MDA-MB-435 tumor growth and inhibited lung metastasis. Thus, we have shown for the first time that a novel small-molecule interacts specifically with the PEX domain of MMP-9 and inhibits tumor growth and metastasis by reducing cell migration and proliferation.

©2011 AACR.

PMID:
21646471
[PubMed - indexed for MEDLINE]
PMCID:
PMC3138841
Free PMC Article

Images from this publication.See all images (7)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk