发现ORIC-533,一种口服生物可用的CD73抑制剂,在高AMP环境中保持活性,以逆转瘤免疫抑制
Jared T Moore1, Hiroyuki Kawai1, Brian R Blank1
1ORIC Pharmaceuticals, Inc., 240 East Grand Avenue, Fl2, South San Francisco, California 94080, United States.
Journal of medicinal chemistry
|October 26, 2025
概括
抑制CD73可降低瘤中的免疫抑制性腺,增强T细胞活性. 强效的CD73抑制剂ORIC-533在临床前模型中显示出瘤生长抑制,目前正在临床试验中.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 药用化学 医学化学
背景情况:
- 由AMP产生的CD73产生的腺素 (ADO) 抑制瘤微环境免疫力,与癌症预后不佳相关.
- 向CD73以降低ADO水平提供了一种扭转瘤免疫抑制的策略.
研究的目的:
- 发现和描述用于癌症免疫治疗的新型CD73抑制剂.
- 为了评估ORIC-533的临床前疗效,一个强大的CD73抑制剂.
主要方法:
- 生物化学和细胞测试以确定ORIC-533对CD73.3的功效.
- 在体外评估对T细胞和细胞因子生产的免疫调节作用.
- 在体内研究使用合成的小鼠癌症模型来评估瘤生长抑制和药理动力学效应.
主要成果:
- ORIC-533在人类和小鼠细胞系中表现出亚纳米级生物化学效能和强大的细胞活性对抗CD73.
- 化合物6在纳米分子度下有效地挽救了T细胞激活和细胞因子生产.
- 口服ORIC-533降低了瘤ADO水平,增加了CD8+T细胞,并在体内抑制了瘤生长.
结论:
- ORIC-533是一种强效,口服可生物利用的CD73抑制剂,具有显著的免疫调节和抗瘤活性.
- 这些发现支持ORIC-533作为治疗癌症,包括多发性骨髓瘤的最佳治疗药物的潜力.
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