title: Small-molecule anticancer compounds selectively target the hemopexin domain of matrix metalloproteinase-9.
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.
authors.affiliation: Departments of Medicine, Chemistry, Molecular and Cellular Biology, and Applied Mathematics, and Bioinformatics Facility, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Dufour
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Sampson
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Cem
authors.initials: C
authors.lastname: Kuscu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rizzo
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Deleon
authors.forename: Jizu
authors.initials: J
authors.lastname: Zhi
authors.forename: Nadia
authors.initials: N
authors.lastname: Jaber
authors.forename: Eric
authors.initials: E
authors.lastname: Liu
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D019556:COS Cells; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002522:Chlorocebus aethiops; D006466:Hemopexin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D006466:Hemopexin; D020780:Matrix Metalloproteinase 9