Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase
Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase
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DOI：
10.1021/acs.jmedchem.9b01255
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发表时间：
2019-12-12
影响因子：
7.3
通讯作者：
Huang, Rong
中科院分区：
文献类型：
--
作者：
Chen, Dongxing;Li, Linjie;Huang, Rong
烟酰胺N-甲基转移酶（NNMT）催化甲基从辅因子S-腺苷甲硫氨酸转移到烟酰胺和其他含吡啶化合物。NNMT是烟酰胺代谢和甲基化潜力的重要调节剂。NNMT的异常表达水平与癌症、代谢和神经退行性疾病有关，这使得NNMT成为潜在的治疗靶点。因此，有效的和选择性的NNMT抑制剂可以作为有价值的工具，研究NNMT在其介导的疾病中的作用。在此，我们采用合理的策略，通过一个新的炔丙基连接体来设计和合成紧密结合的双底物抑制剂LL 320。LL 320的Ki值为1.6 +/- 0.3 nM，是迄今为止最有效的抑制剂。LL 320的共晶结构证实了其与NNMT上的底物和辅因子结合位点的相互作用。重要的是，这是第一个使用炔丙基接头构建有效的甲基转移酶抑制剂的例子，这将扩大我们对甲基转移过渡态的理解。
Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer from the cofactor S-adenosylmethionine to nicotinamide and other pyridine-containing compounds. NNMT is an important regulator for nicotinamide metabolism and methylation potential. Aberrant expression levels of NNMT have been implicated in cancer, metabolic, and neurodegenerative diseases, which makes NNMT a potential therapeutic target. Therefore, potent and selective NNMT inhibitors can serve as valuable tools to investigate the roles of NNMT in its mediated diseases. Here, we applied a rational strategy to design and synthesize the tight-binding bisubstrate inhibitor LL320 through a novel propargyl linker. LL320 demonstrates a K-i value of 1.6 +/- 0.3 nM, which is the most potent inhibitor to date. The cocrystal structure of LL320 confirms its interaction with both the substrate and cofactor binding sites on NNMT. Importantly, this is the first example of using the propargyl linker to construct potent methyltransferase inhibitors, which will expand our understanding of the transition state of methyl transfer.