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Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment

文献类型：期刊论文

作者Sun, Yaoliang7; Chen, Manman5,6; Han, Yuyan5,7; Li, Weiqiang4,5; Ma, Xiaoyu5,6; Shi, Zihan5,7; Zhou, Yang3; Xu, Lan6; Yu, Lei2; Wang, Yuxiang6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-02-22
卷号67期号:5页码:3986-4006
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c02288
通讯作者Meng, Linghua(lhmeng@simm.ac.cn) ; Xu, Shilin(slxu@simm.ac.cn)
英文摘要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.
资助项目China Postdoctoral Science Foundation
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001183217600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310208]  
专题中国科学院上海药物研究所
通讯作者Meng, Linghua; Xu, Shilin
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Tongji Univ, Canc Ctr, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200092, Peoples R China
3.Jinan Univ, Guangzhou City Key Lab Precis Chem Drug Dev, Int Cooperat Lab Tradit Chinese Med Modernizat &, State Key Lab Bioact Mol & Druggabil Assessment,S, Guangzhou 510632, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Yaoliang,Chen, Manman,Han, Yuyan,et al. Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(5):3986-4006.
APA Sun, Yaoliang.,Chen, Manman.,Han, Yuyan.,Li, Weiqiang.,Ma, Xiaoyu.,...&Xu, Shilin.(2024).Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment.JOURNAL OF MEDICINAL CHEMISTRY,67(5),3986-4006.
MLA Sun, Yaoliang,et al."Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment".JOURNAL OF MEDICINAL CHEMISTRY 67.5(2024):3986-4006.

入库方式： OAI收割

来源：上海药物研究所

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