Lee Sang-Yong, Müller Christa E
PharmaCenter Bonn , Pharmaceutical Institute , Pharmaceutical Chemistry I , University of Bonn , An der Immenburg 4 , D-53121 Bonn , Germany . Email:
Medchemcomm. 2017 Feb 9;8(5):823-840. doi: 10.1039/c7md00015d. eCollection 2017 May 1.
Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, EC 3.1.4.1) is a metalloenzyme that belongs to the NPP family, which comprises seven subtypes (NPP1-7). NPP1 hydrolyzes a wide range of phosphodiester bonds, in nucleoside triphosphates, (cyclic) dinucleotides, and nucleotide sugars yielding nucleoside 5'-monophosphates as products. Its main substrate is ATP which is cleaved to AMP and diphosphate. The enzyme is involved in various biological processes including bone mineralization, soft-tissue calcification, insulin receptor signalling, cancer cell proliferation and immune modulation. Therefore, NPP1 inhibitors have potential as novel drugs, for (immuno)oncology. In the last two decades several inhibitors of NPP1 derived from nucleotide- or non-nucleotide scaffolds have been developed. The most potent and selective NPP1-inhibitory substrate analog is adenosine 5'-α,β-methylene-γ-thiotriphosphate ( = 20 nM -Nph-5'-TMP, human membrane-bound NPP1). Non-nucleotide-derived NPP1 inhibitors comprise polysulfonates, polysaccharides, polyoxometalates and small heterocyclic compounds. The polyoxometalate [TiWCoO] (PSB-POM141) is the most potent and selective NPP1 inhibitor described to date ( = 1.46 nM ATP, human soluble NPP1); it displays an allosteric mechanism of inhibition and represents a useful pharmacological tool for evaluating the potential of NPP1 as a novel drug target.
胞外核苷酸焦磷酸酶/磷酸二酯酶1（NPP1，EC 3.1.4.1）是一种金属酶，属于NPP家族，该家族包含七个亚型（NPP1 - 7）。NPP1可水解多种磷酸二酯键，包括核苷三磷酸、（环）二核苷酸和核苷酸糖，生成核苷5'-单磷酸作为产物。其主要底物是ATP，ATP被裂解为AMP和二磷酸。该酶参与多种生物学过程，包括骨矿化、软组织钙化、胰岛素受体信号传导、癌细胞增殖和免疫调节。因此，NPP1抑制剂有潜力成为（免疫）肿瘤学领域的新型药物。在过去二十年中，已经开发了几种源自核苷酸或非核苷酸支架的NPP1抑制剂。最有效和选择性最强的NPP1抑制性底物类似物是腺苷5'-α,β-亚甲基-γ-硫代三磷酸（对人膜结合NPP1的Ki = 20 nM -Nph-5'-TMP）。非核苷酸衍生的NPP1抑制剂包括多磺酸盐、多糖、多金属氧酸盐和小杂环化合物。多金属氧酸盐[TiWCoO]（PSB - POM141）是迄今为止描述的最有效和选择性最强的NPP1抑制剂（对人可溶性NPP1的Ki = 1.46 nM ATP）；它显示出变构抑制机制，是评估NPP1作为新型药物靶点潜力的有用药理学工具。
