The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination.
MT1-MMP and MMP2 have been implicated as pro-tumorigenic and pro-metastatic factors in a wide variety of cancers including melanoma. We have previously demonstrated that MT1-MMP is highly expressed in melanoma where it promotes melanoma cell invasion and metastasis in part through the activation of its target MMP2. Given the accessibility of MMPs, as they are either secreted (e.g. MMP2) or membrane-tethered (e.g. MT1-MMP), they represent ideal targets for specific inhibition via small molecules. Here we show that the novel small-molecule inhibitor ND-322 with high selectivity for MT1-MMP and MMP2, effectively inhibits MT1-MMP and MMP2 activity resulting in reduced in vitro melanoma cell growth, migration and invasion. Importantly, these inhibitory effects lead to significant reduction of melanoma tumor growth and metastasis. We further show that while cell migration and invasion could be similarly hampered by specific inhibition of either MT1-MMP or MMP2 via shRNAs, the growth inhibitory activity of ND-322 could only be mirrored by specific inhibition of MT1-MMP. These data support ND-322 as a novel effective inhibitor capable of counteracting both MT1-MMP and MMP2, two key proteases involved in melanoma growth and metastasis. ND-322 may therefore represent a new inhibitor in the repertoire of treatments against melanoma.
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States.
Charles
C
Marusak
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States.
Ian
I
Bayles
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States.
Jun
J
Ma
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States.
Major
M
Gooyit
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States.
Ming
M
Gao
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States.
Mayland
M
Chang
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States. Electronic address: bxb278@case.edu.
Barbara
B
Bedogni
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D013440:Sulfides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
D061965:Matrix Metalloproteinase Inhibitors; C568509:ND 322; D013440:Sulfides; D013450:Sulfones; D001120:Arginine; C013523:ethylene sulfide; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14
Growth; Invasion; MMP2; MT1-MMP; Melanoma; Metastasis; Migration; ND-322
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