发现了第一个强大的PI3K/mTOR双向PROTAC降解器,用于有效调节PI3K/AKT/mTOR路径
Wentao Zhu1, Jian Chen1, Wenqian Zhang1
1School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China.
Journal of medicinal chemistry
|December 3, 2025
概括
研究人员开发了GP262,这是一种用于PI3K/AKT/mTOR通路的新型双目标降解剂. 这种化合物通过抑制瘤生长,显示出治疗乳腺癌和白血病的巨大潜力.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 酸3-激酶 (PI3K) /蛋白激酶B (AKT) /哺乳动物目标的拉巴胺素 (mTOR) 途径对于细胞生长和新陈代谢至关重要.
- 这种途径的失调经常在各种癌症中观察到,突出显示了它在瘤发生中的作用.
研究的目的:
- 设计和合成新的双目标降解剂,同时抑制PI3K和mTOR.
- 在临床前癌症模型中评估这些化合物的疗效和作用机制.
主要方法:
- 一系列双目标降解剂的合成.
- 生物化学试验以确定对PI3K和mTOR的降解强度 (DC50).
- 在乳腺癌细胞系中进行基于细胞的增殖测试.
- 乌比奎丁-蛋白酶体系统 (UPS) 分析.
- 定量蛋白质组学 (DIA) 和RNA测序 (RNA-seq).
- 在体内抑制瘤生长的研究.
主要成果:
- 化合物GP262被确定为PI3K和mTOR的强有力的双降解剂.
- 在多个乳腺癌细胞系中,GP262表现出显著的抗增殖活性.
- 经证实,通过无素-蛋白酶体系统 (UPS) 发生降解.
- 确认了对位路径的调节,蛋白质组学和RNA-seq.建议具有潜在的抗白血病活性.
- 在体内,GP262显示出显著的瘤生长抑制.
结论:
- GP262是第一个双向的PI3K和mTOR降解剂.
- 这种新型化合物在乳腺癌和白血病治疗中表现出有前途的治疗潜力.
- 对于GP262的临床应用,需要进一步对其进行研究.
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