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Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-07-12 , DOI: 10.1021/acs.jmedchem.9b00413 Yongzhi Gao 1 , Matthijs J van Haren 1 , Ed E Moret , Johannes J M Rood , Davide Sartini 2 , Alessia Salvucci 2 , Monica Emanuelli 2 , Pierrick Craveur 3 , Nicolas Babault 3, 4 , Jian Jin 4 , Nathaniel I Martin 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-07-12 , DOI: 10.1021/acs.jmedchem.9b00413 Yongzhi Gao 1 , Matthijs J van Haren 1 , Ed E Moret , Johannes J M Rood , Davide Sartini 2 , Alessia Salvucci 2 , Monica Emanuelli 2 , Pierrick Craveur 3 , Nicolas Babault 3, 4 , Jian Jin 4 , Nathaniel I Martin 1
Affiliation
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Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N-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.
中文翻译：
具有增强活性的烟酰胺N-甲基转移酶（NNMT）的双底物抑制剂。
烟酰胺N-甲基转移酶（NNMT）催化烟酰胺的甲基化以形成N-甲基烟酰胺。NNMT的过度表达与多种疾病（包括许多癌症和代谢紊乱）有关，这表明NNMT作为潜在的治疗靶标具有重要作用。通过对先前在我们小组中开发的NNMT抑制剂的结构进行修饰，我们制备了多种抑制剂库来探测酶活性位点的不同区域。这项研究表明，旨在通过π-π堆积相互作用结合疏水烟酰胺结合口袋的萘部分的引入显着提高了双底物样NNMT抑制剂的活性（半数最大抑制浓度为1.41μM）。这些发现得到了等温滴定量热结合试验和模型研究的进一步支持。在本研究中鉴定出的最具活性的NNMT抑制剂对HSC-2人口腔癌细胞系的细胞增殖表现出剂量依赖性抑制作用。
更新日期：2019-07-02
中文翻译：
具有增强活性的烟酰胺N-甲基转移酶（NNMT）的双底物抑制剂。
烟酰胺N-甲基转移酶（NNMT）催化烟酰胺的甲基化以形成N-甲基烟酰胺。NNMT的过度表达与多种疾病（包括许多癌症和代谢紊乱）有关，这表明NNMT作为潜在的治疗靶标具有重要作用。通过对先前在我们小组中开发的NNMT抑制剂的结构进行修饰，我们制备了多种抑制剂库来探测酶活性位点的不同区域。这项研究表明，旨在通过π-π堆积相互作用结合疏水烟酰胺结合口袋的萘部分的引入显着提高了双底物样NNMT抑制剂的活性（半数最大抑制浓度为1.41μM）。这些发现得到了等温滴定量热结合试验和模型研究的进一步支持。在本研究中鉴定出的最具活性的NNMT抑制剂对HSC-2人口腔癌细胞系的细胞增殖表现出剂量依赖性抑制作用。
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