Developing an Irreversible Inhibitor of Human DDAH-1, an Enzyme Upregulated in Melanoma

作者：Wang Yun^*; Hu Shougang; Gabisi Abdul M Jr; Er Joyce A V; Pope Arthur; Burstein Gayle; Schardon Christopher L; Cardounel Arturo J; Ekmekcioglu Suhendan; Fast Walter

来源：ChemMedChem, 2014, 9(4): 792-797.

DOI：10.1002/cmdc.201300557

• covalent inhibitors
• dimethylaminohydrolase
• dimethylarginine
• melanoma
• nitric oxide

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 (K-I=1.3 +/- 0.6M; k(inact)=0.34 +/- 0.07min(-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 +/- 0.2M) 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.

• 出版日期2014-4