ENPP1在肿瘤中的作用及其抑制剂的研究进展

Advances of ENPP1 in tumor and its inhibitors applied in tumor therapy

外核苷酸焦磷酸酶/磷酸二酯酶(ecto-nucleotide pyrophosphatases/phosphodiesterases,ENPPs)参与一系列生理过程中不同嘌呤核苷酸的水解。最近几年发现其也参与肿瘤进展,ENPP1在肿瘤中的作用主要集中在肿瘤增殖、转移、免疫、复发等方面,而且推测ENPP1可作为多种肿瘤的预后指标。ENPP1通过参与调控ATP/腺苷平衡来促进免疫抑制肿瘤微环境,其与干扰素基因刺激因子交叉,通过水解效应子2′,3′-环GMP-AMP损害其强大的免疫反应。因此,ENPP1阻断成为引发免疫重塑,抑制肿瘤发生发展的有效手段。现有的ENPP1抑制剂主要包括天然小分子化合物、核苷酸类、非核苷酸类ENPP1抑制剂、新型小分子ENPP1抑制剂。迄今为止,已开发的少量ENPP1抑制剂较少用于体内实验,尚处于开发出有效的化合物或先导化合物阶段,关于ENPP1抑制剂的研究还有待深入。该文总结并讨论了ENPP1在肿瘤中的作用,并汇总了现有的各类ENPP1抑制剂及其研究进展,以期为进一步制备候选药物研究提供参考。

Ecto-nucleotide pyrophosphatases/phosphodiesterases(ENPPs)are involved in the hydrolysis of different purine nucleotides in a range of physiological processes.In recent years,it has also been found to be involved in tumor progression,with ENPP1 often overexpressed in local recurrence and tumor metastasis,which is associated with poor prognosis and survival in a range of solid tumors.The role of ENPP1 in tumors is mainly focused on tumor proliferation,metastasis,immunity,recurrence,etc.,and it is speculated that ENPP1 can be used as a prognostic indicator for a variety of tumors.ENPP1 promotes the immunosuppressive tumor microenvironment by being obliquely involved in the regulation of ATP/adenosine homeostasis by combining with other components,which crosses with interferon gene stimulators to impair its potent immune response through the hydrolysis of the effector 2′,3′-cyclic GMP-AMP.Therefore,ENPP1 blockade has become an effective means to induce immune remodeling and inhibit tumorigenesis and development.The existing ENPP1 inhibitors mainly include natural small molecule compounds,nucleotide ENPP1 inhibitors,non-nucleotide ENPP1 inhibitors,and novel small molecule ENPP1 inhibitors.So far,a small number of ENPP1 inhibitors have been developed and are rarely suitable for in vivo experiments,and they are still in the stage of developing effective compounds or lead compounds,and the research on ENPP1 inhibitors needs to be further studied.This review summarizes and discusses the role of ENPP1 in tumors,and summarizes the current research progress of various ENPP1 agents and their current research progress,in order to provide a reference for further research on the preparation of drug candidates.