基于TNA-DNA双对应结合剂的c- Myc- Targeting PROTAC用于三阴性乳腺癌的联合治疗
Xintong Li1, Ze Zhang2, Fangyan Gao1
1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Journal of the American Chemical Society
|April 17, 2023
概括
研究人员开发了一种新型的核酸PROTAC来降解c-Myc,这是侵袭性三阴性乳腺癌 (TNBC) 的目标. 这种治疗方法对TNBC治疗和药物开发具有前景.
科学领域:
- 生物化学
- 分子生物学
- 癌症治疗方法
背景情况:
- 三重阴性乳腺癌 (TNBC) 是一种缺乏向治疗的侵袭性亚型.
- 这种c-Myc瘤蛋白是TNBC的关键驱动因素,也是潜在的治疗点.
- 目前TNBC的治疗策略有限,需要新的治疗方法.
研究的目的:
- 开发一种基于核酸的新型化向基因组 (PROTAC) 来降解c-Myc基蛋白.
- 评估开发的PROTAC在抑制TNBC细胞增殖和使细胞对现有疗法的有效性.
- 在临床前TNBC模型中评估PROTAC的治疗潜力.
主要方法:
- 选择一个针对c-Myc/Max异构体的TNA (三核酸) 合体.
- 结合TNA胺与E盒DNA序列和利胺,形成双价PROTAC (TEP).
- 在体外评估TEP介导的c- Myc/ Max降解,TNBC细胞增殖抑制和药物敏感性.
- 在小鼠TNBC模型中对TEP和palbociclib联合治疗的体内评估.
主要成果:
- TNA-E盒子-波马利多胺 (TEP) 结合剂有效地向并降解内源性c-Myc/Max.
- 在体外,TEP显著抑制了TNBC细胞的增殖.
- TEP使TNBC细胞对依赖于环素的激酶抑制剂palbociclib产生敏感性.
- 在小鼠TNBC模型中,TEP和palbociclib的联合治疗有效抑制瘤生长.
结论:
- 基于核酸的PROTAC是针对TNBC等侵袭性癌症的一种可行的方法.
- 开发的TEP结合物显示出对TNBC的显著治疗潜力.
- 这种方法为TNBC的化学生物学研究和未来的临床干预提供了有希望的策略.
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