开发DOT1L向蛋白质降解剂,用于治疗MLL-r白血病
Songhua Quan1,2, Kenji Unno1,2, Dikshat G Gupta1,2
1Department of Urology, Northwestern University Feinberg School of Medicine; Chicago, Illinois 60611, United States.
Journal of medicinal chemistry
|February 13, 2026
概括
新的蛋白质分解向嵌合体 (PROTACs) 有效降解DOT1L,这是MLL重组白血病的关键驱动因素. 这种蛋白质降解方法在治疗抗性白血病形式方面显示出前景.
科学领域:
- 血液学 血液学 血液学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- DOT1L是MLL重排列 (MLL-r) 白血病中的关键瘤原因驱动因素.
- 现有的催化抑制剂已经显示出有限的临床疗效.
- 对于白血病的进展来说,DOT1L的非酶功能至关重要.
研究的目的:
- 开发新的DOT1L向PROTAC来降解DOT1L并抑制其功能.
- 评估这些PROTACs在MLL-r白血病模型中的疗效.
主要方法:
- 针对DOT1L的PROTAC的开发和描述 (DOT1L705和DOT1L808).
- 评估PROTACs的功效和选择性.
- 对DOT1L705对白血病细胞活性的影响的评估,包括抗敏抑制剂的细胞.
- 在体内对DOT1L808的研究,用于正位白血病模型.
主要成果:
- DOT1L705和DOT1L808表明DOT1L具有强大和选择性的降解 (DC50值低至5nM).
- DOT1L705显示有效性取决于MLL-r状态,并保留了对抗性细胞的活性.
- DOT1L808在体内实现了完全的瘤回归,没有显著的毒性.
结论:
- 通过PROTACs降解蛋白质是MLL-r白血病的可行的治疗策略.
- 针对DOT1L的PROTAC提供了一种有希望的方法来克服当前治疗方法的局限性.
相关概念视频
02:58Regulated Protein Degradation
8.9K
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...
8.9K
02:58Regulated Protein Degradation
3.2K
3.2K
02:11Proteins: From Genes to Degradation
14.6K
Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick. Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
Transcription is the synthesis of RNA...
Transcription is the synthesis of RNA...
14.6K
02:11Proteins: From Genes to Degradation
4.6K
4.6K
01:57Protein Complexes with Interchangeable Parts
3.0K
Groups of proteins may form a complex where each protein in this complex has a different role in the overall execution of the complex’s function. Often some of the proteins in the complex can be replaced by a closely related variant to give a complex that contains many of the same components yet is functionally distinct.
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
3.0K
02:18Intrinsically Disordered Proteins
19.6K
Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be...
19.6K