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Developing an irreversible inhibitor of human DDAH-1, an enzyme upregulated in melanoma.

Authors
Type
Published Article
Journal
ChemMedChem
1860-7179
Publisher
Wiley Blackwell (John Wiley & Sons)
Publication Date
Volume
9
Issue
4
Pages
792–797
Identifiers
DOI: 10.1002/cmdc.201300557
PMID: 24574257
Source
Medline
Keywords
  • Covalent Inhibitors
  • Dimethylaminohydrolase
  • Dimethylarginine
  • Melanoma
  • Nitric Oxide

Abstract

Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH-1) can raise endogenous levels of asymmetric dimethylarginine (ADMA) and lead to a subsequent inhibition of nitric oxide synthesis. In this study, N(5) -(1-imino-2-chloroethyl)-L-ornithine (Cl-NIO) is shown to be a potent time- and concentration-dependent inhibitor of purified human DDAH-1 (KI =1.3±0.6 μM; kinact =0.34±0.07 min(-1) ), with >500-fold selectivity against two arginine-handling enzymes in the same pathway. An activity probe is used to measure the "in cell" IC50 value (6.6±0.2 μM) for Cl-NIO inhibition of DDAH-1 artificially expressed within cultured HEK293T cells. A screen of diverse melanoma cell lines reveals that a striking 50/64 (78 %) of melanoma lines tested showed increased levels of DDAH-1 relative to normal melanocyte control lines. Treatment of the melanoma A375 cell line with Cl-NIO shows a subsequent decrease in cellular nitric oxide production. Cl-NIO is a promising tool for the study of methylarginine-mediated nitric oxide control and a potential therapeutic lead compound for other indications with elevated nitric oxide production, such as septic shock and idiopathic pulmonary fibrosis.

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