针对细胞选择性和向性降解激活的STAT3的Oligo-PROTAC战略
bioRxiv : the preprint server for biology
|August 14, 2023
概括
这项研究开发了一种新型的蛋白质分解向化体 (PROTAC) 来降解癌症中的关键蛋白质STAT3. 在临床前模型中,STAT3D PROTAC证明了细胞选择性向,并有效地减少了淋巴瘤的生长.
科学领域:
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
- 药物发现 药物发现 药物发现
背景情况:
- 诱-寡度氧核化物 (D-ODN) 显示出针对STAT3等转录因子的潜力,但面临着交付和功效的挑战.
- STAT3是各种癌症的关键调节剂,使其成为一个有吸引力的治疗点.
- 目前针对STAT3的策略受到交付和特异性问题的限制.
研究的目的:
- 开发一种新型的向蛋白解的嵌合体 (PROTAC),用于针对性地降解STAT3.
- 通过使用 PROTAC 技术,增强 STAT3 向 D-ODN 的交付和功效.
- 在临床前癌症模型中评估STAT3D PROTAC结合物的治疗潜力.
主要方法:
- 将一个STAT3特异性的D-ODN与thalidomide (Tha) 结合,以创建STAT3D PROTAC.
- 使用计算建模来预测STAT3无处不在的位置.
- 通过将STAT3D PROTAC与CpG配体结合,开发一个髓状细胞/B细胞选择性结合体 (C-STAT3D PROTAC).
- 在细胞和异种移植模型中评估STAT3下调,基因调节和抗瘤疗效.
主要成果:
- 在目标细胞中,STAT3D PROTAC有效降低了STAT3的调节,对STAT1和STAT5.5具有特异性.
- 计算机建模确定K601和K626为STAT3D PROTAC活动的关键无处不在地点.
- C-STAT3D PROTAC显示了TLR9+细胞的选择性内化和骨髓细胞和淋巴瘤细胞中显著的STAT3减少.
- C-STAT3D PROTAC治疗导致STAT3基因 (BCL2L1,CCND2,MYC) 的下调,并在体内触发了淋巴瘤回归.
结论:
- 对于细胞选择性向和使用诱寡核酸降解STAT3,PROTAC策略是可行的.
- STAT3D PROTAC及其结合物C-STAT3D PROTAC为癌症治疗提供了一个有前途的方法,特别是在淋巴瘤治疗中.
- 这种方法有可能针对STAT3.3以外的其他瘤原性转录因子.
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