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发现了一种非酶功能的蛋白质氨酸甲基转移酶1 (PRMT1) 降解剂的第一类研究
Chenning Ma1, Hanyin Sun1, Chang Shen1
1Shanghai Frontiers Science Center of Targeted Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China.
European journal of medicinal chemistry
|April 17, 2025
概括
研究人员开发了CM112,这是第一个蛋白质氨酸甲基转移酶1 (PRMT1) 降解剂,用于向癌症. CM112选择性降解PRMT1,为研究其非酶功能和治疗PRMT1驱动疾病提供了一个新的工具.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 药用化学 医学化学
背景情况:
- 蛋白质氨酸甲基转移酶1 (PRMT1) 对于不对称的氨酸二甲基化至关重要,并与癌症和炎症有关.
- 现有的PRMT1抑制剂缺乏选择性,并在临床试验中显示出有限的疗效和毒性.
- PRMT1的非酶功能,特别是其对孤儿受体TR3稳定性的调节,尚未得到充分研究.
研究的目的:
- 设计,合成和描述一种新的,一流的PRMT1降解剂.
- 评估PRMT1降解剂在癌细胞系中的选择性和有效性.
- 为了研究降解剂针对PRMT1非酶功能的潜力.
主要方法:
- 通过PEG链接器将阿达曼坦与MS023连接起来,设计和合成CM112.
- 在各种固体癌细胞系中评估PRMT1降解.
- 与其他I型PRMT相比,PRMT1选择性的评估 (PRMT3/4/6).
- 在小鼠中的药理动力学研究.
主要成果:
- CM112在癌细胞中显示了依赖于度和时间的PRMT1降解.
- 相对于其他I型PRMT,CM112对PRMT1降解具有很高的选择性.
- 通过降低TR3稳定性,CM112成功地准了PRMT1的非酶功能.
- 在小鼠中观察到CM112的有利生物可用性.
结论:
- CM112是第一个强效和选择性的PRMT1降解剂,为研究PRMT1的非酶作用提供了有价值的工具.
- CM112能够准PRMT1的非酶功能,为PRMT1驱动的疾病提供了一种新的治疗策略.
- 这项研究为开发更强效和类似药物的PRMT1降解剂为未来的治疗应用铺平了道路.
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