系统性STING激活非核酸cGAMP模拟剂的抗瘤活性
Emily N Chin1, Chenguang Yu1,2, Vincent F Vartabedian3
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science (New York, N.Y.)
|August 22, 2020
概括
研究人员发现了SR-717,它是干扰素基因刺激 (STING) 途径的小分子激动剂. 这种化合物具有抗瘤作用,并增强免疫细胞的激活,为不稳定的天然配体提供了有希望的替代品.
科学领域:
- 免疫学
- 药理学
- 结构生物学
背景情况:
- 干扰素基因刺激剂 (STING) 对于先天免疫至关重要,它将免疫反应与抗瘤免疫等过程联系起来.
- 目前对STING抗癌潜力的理解受到其天然循环二核酸 (CDN) 配体的代谢不稳定性阻碍.
研究的目的:
- 识别和描述一种新型的,代谢稳定的小分子激动剂.
- 探索这种激动剂在癌症治疗中的治疗潜力.
主要方法:
- 基于细胞选的向途径以识别STING激动剂.
- 结晶学以确定结合方式和作用机制.
- 评估抗瘤活性和免疫细胞激活的体内研究.
主要成果:
- 鉴定了SR-717,一种具有广泛特异性的非核酸小分子STING激动剂.
- 结构分析显示SR-717作为循环氨酸单酸-氨酸单酸 (cGAMP) 仿真剂,诱导一个封闭的STING构造.
- SR-717表现出显著的抗瘤活性,促进了CD8+T,NK和树突细胞的激活,并促进了抗原交叉激活.
- 由SR-717诱导的编程细胞死亡1联体1 (PD- L1) 的STING依赖表达.
结论:
- SR-717是一种有前途的,稳定的小分子STING激动剂,具有治疗癌症免疫疗法的潜力.
- 由于SR-717能够激活先天性和适应性免疫细胞并诱导PD-L1表达,因此需要进一步研究临床应用.
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