5,7-二氢- 6h -吡咯[2,3-d]嘧啶-6- 1衍生物在STING途径介导的免疫治疗中作为ENPP1抑制剂的鉴定

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-07-25 DOI:10.1021/acs.jmedchem.5c01021

Su Hyun Ji,Miso Kang,Hyomin Ahn,Soo Yeon Baek,In-Gyun Lee,Hanul Jeon,Hwan Won Chung,Dong Kyun Han,Seoyeong Yang,Hyebin Lee,Yeseul Kim,Ji Hun Wi,Jeehee Lee,Younghun Yoo,Sungbae Kang,Mihue Jang,Byungsun Jeon,Nam-Jung Kim,Chiman Song,Sanghee Lee,Seo-Jung Han

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引用次数: 0

摘要

发现了一种新型的小分子ENPP1抑制剂，化合物31具有一个pyrorolopy嘧啶酮核心。化合物31对ENPP1具有较强的抑制作用，IC50值为14.68 nM，有效激活了细胞中的STING通路。此外，31促进细胞因子的释放，从而增强先天免疫反应。此外，31个表现出良好的ADMET性质。化合物31对4T1和CT26小鼠模型均有明显的抗肿瘤作用，且无明显毒性。这些发现强调了31作为一种有前景的化合物，通过增强sting介导的免疫激活和改善对免疫检查点抑制剂的反应，具有癌症免疫治疗的潜力。

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Identification of 5,7-Dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one Derivatives as ENPP1 Inhibitors for STING Pathway-Mediated Immunotherapy.

A novel small-molecule ENPP1 inhibitor, compound 31 featuring a pyrrolopyrimidinone core, was identified. Compound 31 exhibited potent ENPP1 inhibition with an IC50 of 14.68 nM and effectively activated the STING pathway in cell lines. In addition, 31 promoted cytokine release, thereby enhancing innate immune response. Moreover, 31 demonstrated favorable ADMET properties. Compound 31 displayed significant antitumor efficacy in 4T1 and CT26 syngeneic mouse models without notable toxicity. These findings highlight the potential of 31 as a promising compound for cancer immunotherapy by enhancing STING-mediated immune activation and improving responses to immune checkpoint inhibitors.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.