通过IMiD独立的指域准转录因子
bioRxiv : the preprint server for biology
|January 23, 2024
概括
研究人员发现了一种新药,SH6,它降解了癌症驱动因素SALL4蛋白. 这种独立于IMID的方法表明,通过准一种新的指降解来治疗表达SALL4的癌症具有前途.
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:
- 免疫调节性伊米德药物 (IMiDs) 针对癌症治疗的转录因子中的C2H2指降解子.
- 萨尔4是一种具有多个C2H2指的癌症驱动物,但它不是现有的IMID有效的目标.
研究的目的:
- 开发一种与IMID药物独立的针对SALL4表达性癌症的新型治疗策略.
- 确定和描述一种针对SALL4.4中非IMiD降解子的新药.
主要方法:
- 使用AlphaFold和ZFC4-DNA晶体结构来识别药物口袋.
- 在接和细胞活力测试中使用,以选化学库.
- 进行了包括蛋白质降解试验和体内异种移植模型在内的机制研究.
主要成果:
- 发现SH6,一种选择性向SALL4表达癌细胞的化合物.
- 通过依赖ZFC4域的CUL4A/CRBN通路,SH6通过SALL4进行降解.
- SH6在体内显著抑制瘤生长 (62%) 和良好的药理动力学.
结论:
- 这项研究提出了一种新的IMID独立药物发现方法,针对C2H2转录因子.
- SH6代表了对SALL4驱动癌症的有前途的治疗候选者.
相关概念视频
Transcription Factors
75.8K
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
75.8K
Eukaryotic Transcription Inhibitors
9.8K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
9.8K
Eukaryotic Transcription Activators
11.0K
Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
11.0K
General Transcription Factors
5.3K
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
5.3K
Master Transcription Regulators
6.9K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
6.9K
RNA Polymerase II Accessory Proteins
9.2K
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
9.2K


