化学
干扰素基因刺激剂
磷酸二酯酶
癌症免疫疗法
角色扮演
环磷酸鸟苷
药理学
体内
癌细胞
癌症
酶
免疫疗法
生物化学
生物
内科学
医学
生物技术
有机化学
一氧化氮
胞浆
作者
Yaoliang Sun,Man Chen,Yuyan Han,Weiqiang Li,Xiaoyu Ma,Zihan Shi,Yang Zhou,Lan Xu,Lei Yu,Yuxiang Wang,Jinghua Yu,Xingxing Diao,Linghua Meng,Shilin Xu
标识
DOI:10.1021/acs.jmedchem.3c02288
摘要
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an extracellular enzyme responsible for hydrolyzing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), the endogenous agonist for the stimulator of interferon genes (STING) pathway. Inhibition of ENPP1 can trigger STING and promote antitumor immunity, offering an attractive therapeutic target for cancer immunotherapy. Despite progress in the discovery of ENPP1 inhibitors, the diversity in chemical structures and the efficacy of the agents are far from desirable, emphasizing the demand for novel inhibitors. Herein, we describe the design, synthesis, and biological evaluation of a series of ENPP1 inhibitors based on the pyrido[2,3-d]pyrimidin-7-one scaffold. Optimization efforts led to compound 31 with significant potency in both ENPP1 inhibition and STING pathway stimulation in vitro. Notably, 31 demonstrated in vivo efficacy in a syngeneic 4T1 mouse triple negative breast cancer model. These findings provide a promising lead compound with a novel scaffold for further drug development in cancer immunotherapy.
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