Developing an Irreversible Inhibitor of Human DDAH‐1, an Enzyme Upregulated in Melanoma. Issue 4 (26th February 2014)

• Record Type: Journal Article
• Authors: Wang, Yun; Hu, Shougang; Gabisi, Abdul M.; Er, Joyce A. V.; Pope, Arthur; Burstein, Gayle; Schardon, Christopher L.; Cardounel, Arturo J.; Ekmekcioglu, Suhendan; Fast, Walter
• Is Part Of: ChemMedChem. Volume 9:Issue 4(2014:Apr.)
• Page Start: 792
• Page End: 797
• Publication Date: 2014-02-26
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300557
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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, <italic>N</italic>⁵‐(1‐imino‐2‐chloroethyl)‐<sc>L</sc>‐ornithine (Cl‐NIO) is shown to be a potent time‐ and concentration‐dependent inhibitor of purified human DDAH‐1 (<italic>K</italic>_I=1.3±0.6 μ<sc>M</sc>; <italic>k</italic>_inact=0.34±0.07 min⁻¹), with &gt;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 μ<sc>M</sc>) 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.</p> </abstract>