title: Novel MT1-MMP small-molecule inhibitors based on insights into hemopexin domain function in tumor growth.
abstract: Membrane type-1 matrix metalloproteinase (MT1-MMP) is a promising drug target in malignancy. The structure of MT1-MMP includes the hemopexin domain (PEX) that is distinct from and additional to the catalytic domain. Current MMP inhibitors target the conserved active site in the catalytic domain and, as a result, repress the proteolytic activity of multiple MMPs instead of MT1-MMP alone. In our search for noncatalytic inhibitors of MT1-MMP, we compared the protumorigenic activity of wild-type MT1-MMP with an MT1-MMP mutant lacking PEX (ΔPEX). In contrast to MT1-MMP, ΔPEX did not support tumor growth in vivo, and its expression resulted in small fibrotic tumors that contained increased levels of collagen. Because these findings suggested an important role for PEX in tumor growth, we carried out an inhibitor screen to identify small molecules targeting the PEX domain of MT1-MMP. Using the Developmental Therapeutics Program (National Cancer Institute/NIH), virtual ligand screening compound library as a source and the X-ray crystal structure of PEX as a target, we identified and validated a novel PEX inhibitor. Low dosage, intratumoral injections of PEX inhibitor repressed tumor growth and caused a fibrotic, ΔPEX-like tumor phenotype in vivo. Together, our findings provide a preclinical proof of principle rationale for the development of novel and selective MT1-MMP inhibitors that specifically target the PEX domain.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Remacle
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Shiryaev
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Chernov
authors.forename: Anton V
authors.initials: AV
authors.lastname: Cheltsov
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D005260:Female; D006466:Hemopexin / Q000737:chemistry*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D023041:Xenograft Model Antitumor Assays
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D006466:Hemopexin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14