Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009, Nanjing, China.
Peking University Shenzhen Graduate School, Shenzhen, China.
Eur J Med Chem. 2024 Mar 5;267:116211. doi: 10.1016/j.ejmech.2024.116211. Epub 2024 Feb 10.
The cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2', 3'-cGAMP and reduce extracellular 2', 3'-cGAMP concentration. ENPP1 has been validated to play important roles in diabetes, cancers, and cardiovascular disease and now become a promising target for tumor immunotherapy. Several ENPP1 inhibitors under development have shown good anti-tumor effects alone or in combination with other agents in clinical and preclinical researches. In this review, the biological profiles of ENPP1 were described, and the structures and the structure-activity relationships (SAR) of the known ENPP1 inhibitors were summarized. This review also provided the prospects and challenges in the development of ENPP1 inhibitors.
近年来，cGAS-STING 通路相关的癌症免疫疗法取得了重大进展。STING 激动剂具有广谱抗肿瘤作用和强烈的免疫反应。作为 cGAS-STING 通路的负调节剂，外核苷酸焦磷酸酶/磷酸二酯酶 1（ENPP1）可以水解细胞外 2'，3'-cGAMP 并降低细胞外 2'，3'-cGAMP 浓度。ENPP1 已被证实在糖尿病、癌症和心血管疾病中发挥重要作用，现已成为肿瘤免疫治疗的一个有前途的靶点。一些正在开发的 ENPP1 抑制剂在临床和临床前研究中单独或与其他药物联合使用显示出良好的抗肿瘤效果。本综述描述了 ENPP1 的生物学特性，并总结了已知的 ENPP1 抑制剂的结构和构效关系（SAR）。本综述还展望了 ENPP1 抑制剂的开发前景和挑战。
