发现了第一类G9a/GLP PROTAC降解器
Julia Velez1, Yulin Han1, Hyerin Yim1
1Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
bioRxiv : the preprint server for biology
|March 11, 2024
概括
我们开发了一种新的PROTAC降解剂,化合物10 (MS8709),可以有效降解G9a/GLP蛋白. 这种新疗法在治疗依赖G9a/GLP活性的癌症方面表现有前途.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 氨基甲基转移酶G9a和GLP的异常表达与癌症的发展有关.
- G9a/GLP既具有催化作用,也具有非催化作用的致癌功能.
- 现有的G9a/GLP催化抑制剂对抗癌疗效有限.
研究的目的:
- 发现和描述一流的G9a/GLP蛋白质分解向化母 (PROTAC) 降解剂.
- 评估这个PROTAC作为抗癌疗法的潜力.
主要方法:
- 开发一种针对G9a/GLP的新型PROTAC分子 (化合物10,MS8709).
- 评价G9a/GLP降解在度,时间和无素-蛋白酶体系统 (UPS) 取决的方式.
- 对G9a/GLP的化合物10对其他甲基转移酶的选择性的评估.
- 通过化合物10对抗各种癌症细胞系中的原始抑制剂 (UNC0642) 的细胞生长抑制的比较.
- 在小鼠中的药理动力学研究.
主要成果:
- 化合物10通过UPS有效诱导G9a/GLP降解.
- 化合物10对G9a/GLP具有选择性,并且不会影响它们的mRNA水平.
- 与UNC0642相比,化合物10在前列腺,白血病和肺癌细胞中表现出优异的细胞生长抑制.
- 化合物10在体内研究中具有有利的小鼠药理动力学特性.
结论:
- 化合物10是第一个具有显著治疗潜力的G9a/GLP PROTAC降解剂.
- 化合物10作为一种有价值的化学生物学工具,用于研究G9a/GLP功能.
- 化合物10在治疗由G9a/GLP活性驱动的癌症方面具有前景.
相关概念视频
02:58Regulated Protein Degradation
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
02:58Regulated Protein Degradation
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
01:12GPCR Desensitization
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...