Biological Chemistry Group, Institute of Biology Leiden , Leiden University , Sylviusweg 72 , 2333 BE Leiden , The Netherlands.
Department of Clinical Sciences , Universitá Politecnica delle Marche , Via Ranieri 65 , 60131 Ancona , Italy.
J Med Chem. 2019 Jul 25;62(14):6597-6614. doi: 10.1021/acs.jmedchem.9b00413. Epub 2019 Jul 12.
Nicotinamide -methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form -methylnicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme's active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic nicotinamide binding pocket via π-π stacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell proliferation of the HSC-2 human oral cancer cell line.
烟酰胺 -N- 甲基转移酶（NNMT）催化烟酰胺的甲基化形成甲基烟酰胺。NNMT 的过表达与多种疾病相关，包括多种癌症和代谢紊乱，这表明 NNMT 可能是一个有治疗潜力的靶点。通过对我们之前在本课题组开发的一种 NNMT 抑制剂进行结构修饰，我们制备了一个多样化的抑制剂文库，以探究酶活性位点的不同区域。这项研究表明，引入萘基部分旨在通过π-π 堆积相互作用与疏水性烟酰胺结合口袋结合，可显著提高双底物样 NNMT 抑制剂的活性（半最大抑制浓度为 1.41 μM）。这些发现得到了等温滴定量热法结合实验和建模研究的进一步支持。在本研究中鉴定出的最有效的 NNMT 抑制剂对人口腔癌细胞系 HSC-2 的细胞增殖表现出剂量依赖性抑制作用。
