癌症免疫疗法
化学
磷酸二酯酶
干扰素基因刺激剂
广告
免疫疗法
体内
干扰素
药理学
生物化学
体外
癌细胞
酶
癌症
癌症研究
免疫系统
生物
胞浆
免疫学
生物技术
遗传学
作者
Mukesh Gangar,Sandeep Goyal,Digambar Raykar,Princy Khurana,Ashwita M. Martis,Avijit Goswami,Ishani Ghoshal,Kinjal A. Patel,Yadav Nagare,Santosh S. Raikar,Arup Mukherjee,Rajath Cyriac,Jean‐François Paquin,Aditya Kulkarni
标识
DOI:10.1016/j.bioorg.2021.105549
摘要
Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.
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