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Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy

文献类型：期刊论文

作者He, Jie3,4; Ma, Xiaoyu2; Sun, Jia3,4; Chen, Manman2; Xu, Lan2; Song, Zilan3,4; Ding, Chunyong3,4; Meng, Linghua2; Zhang, Ao1,3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-02-20
页码18
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c03207
通讯作者Meng, Linghua(lhmeng@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要ENPP1, a transmembrane glycoprotein overexpressed in various cancers, has become a promising target for tumor immunotherapy. Several ENPP1 inhibitors have been reported, but only a few have been validated in vivo. Herein, based on the reported inhibitors 3 and 6, we carried out a structural optimization by designing a variety of 8-methoxyquinazoline and its equivalent 8-methoxy-3-cyano-quinoline derivatives featuring bridged- or spirobicycles as the linker. Compound 30 was identified as a promising ENPP1 inhibitor. This compound exhibited IC50 values of 8.05 nM against ENPP1 and 1.53 nM in MDA-MB-231 cells with no significant inhibitory effects against both hERG and a panel of 97 kinases. It effectively activated the intracellular STING pathway by inhibiting cGAMP degradation. In the murine CT-26 tumor model, 30 inhibited tumor growth with increased immune cell infiltration in the tumor microenvironment and enhanced type I interferon responses. Meanwhile, compound 30 synergically enhanced the antitumor efficacy of anti-PD-L1 antibody.
WOS关键词INNATE ; DISCOVERY
资助项目National Natural Science Foundation of China[82273767] ; National Natural Science Foundation of China[22494694] ; National Natural Science Foundation of China[ZJ2021-ZD-007] ; National Natural Science Foundation of China[Technology-2030] ; National Natural Science Foundation of China[2021ZD0204004] ; Major Projects for Shanghai Zhangjiang National Independent Innovation of China[SKLDR-2024-KF-01] ; State Key Laboratory of Drug Research ; State Key Laboratory of Chemical Biology
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001427041800001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/316308]  
专题中国科学院上海药物研究所
通讯作者Meng, Linghua; Zhang, Ao
作者单位1.Guangdong Med Univ, Dongguan Affiliated Hosp 1, Dongguan 523808, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.Shanghai Jiao Tong Univ, State Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
4.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 He, Jie,Ma, Xiaoyu,Sun, Jia,et al. Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025:18.
APA He, Jie.,Ma, Xiaoyu.,Sun, Jia.,Chen, Manman.,Xu, Lan.,...&Zhang, Ao.(2025).Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy.JOURNAL OF MEDICINAL CHEMISTRY,18.
MLA He, Jie,et al."Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy".JOURNAL OF MEDICINAL CHEMISTRY (2025):18.

入库方式： OAI收割

来源：上海药物研究所

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