The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination

Charles Marusak, Ian Bayles, Jun Ma, Major Gooyit, Ming Gao, Mayland Chang, Barbara Bedogni

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)515-520
Number of pages6
JournalPharmacological Research
Volume113
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 14
Matrix Metalloproteinase Inhibitors
Melanoma
Growth
Neoplasms
Neoplasm Metastasis
Cell Movement
ethylene sulfide
ND 322
Matrix Metalloproteinases
Peptide Hydrolases
Membranes

Keywords

  • Growth
  • Invasion
  • Melanoma
  • Metastasis
  • Migration
  • MMP2
  • MT1-MMP
  • ND-322

ASJC Scopus subject areas

  • Pharmacology

Cite this

The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination. / Marusak, Charles; Bayles, Ian; Ma, Jun; Gooyit, Major; Gao, Ming; Chang, Mayland; Bedogni, Barbara.

In: Pharmacological Research, Vol. 113, 01.11.2016, p. 515-520.

Research output: Contribution to journalArticle

Marusak, Charles ; Bayles, Ian ; Ma, Jun ; Gooyit, Major ; Gao, Ming ; Chang, Mayland ; Bedogni, Barbara. / The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination. In: Pharmacological Research. 2016 ; Vol. 113. pp. 515-520.
@article{ad591a209854448989916edf6c6ecc4a,
title = "The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination",
abstract = "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.",
keywords = "Growth, Invasion, Melanoma, Metastasis, Migration, MMP2, MT1-MMP, ND-322",
author = "Charles Marusak and Ian Bayles and Jun Ma and Major Gooyit and Ming Gao and Mayland Chang and Barbara Bedogni",
year = "2016",
month = "11",
day = "1",
doi = "10.1016/j.phrs.2016.09.033",
language = "English (US)",
volume = "113",
pages = "515--520",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination

AU - Marusak, Charles

AU - Bayles, Ian

AU - Ma, Jun

AU - Gooyit, Major

AU - Gao, Ming

AU - Chang, Mayland

AU - Bedogni, Barbara

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

KW - Growth

KW - Invasion

KW - Melanoma

KW - Metastasis

KW - Migration

KW - MMP2

KW - MT1-MMP

KW - ND-322

UR - http://www.scopus.com/inward/record.url?scp=84989180535&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84989180535&partnerID=8YFLogxK

U2 - 10.1016/j.phrs.2016.09.033

DO - 10.1016/j.phrs.2016.09.033

M3 - Article

VL - 113

SP - 515

EP - 520

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

ER -