开发强效和选择性协活性剂相关的氨酸甲基转移酶1 (CARM1) 降解剂
Haibo Xie1, Megan S Bacabac2, Min Ma1
1Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
Journal of medicinal chemistry
|September 13, 2023
概括
研究人员为CARM1,一种与癌症相关的蛋白质开发了一种针对金马的新型蛋白质分解 (PROTAC). 这种CARM1 PROTAC有效降解细胞中的标蛋白,为CARM1驱动的癌症提供潜在的治疗应用.
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:
- 在许多癌症中,CARM1 (蛋白质氨酸甲基转移酶) 过度表达,与预后不佳相关.
- 现有的小分子CARM1抑制剂显示出有限的细胞疗效.
- 向CARM1是一种有前途的癌症治疗策略.
研究的目的:
- 开发一个针对CARM1.1的蛋白质分解的嵌合体 (PROTAC).
- 评估开发的CARM1 PROTAC的细胞疗效和选择性.
- 研究癌细胞中CARM1降解的功能后果.
主要方法:
- 一个 CARM1 PROTAC (化合物3b) 的设计和合成,包括一个 CARM1 连接体 (TP-064),一个链接体和一个 VHL E3 连接酶连接体.
- 对细胞降解活性 (DC50,Dmax) 和对其他蛋白质氨酸甲基转移酶的选择性进行评估.
- 在基于细胞的试验中评估CARM1基质甲基化和癌细胞迁移抑制.
主要成果:
- 化合物3b在几个小时内显示出强大的CARM1降解 (DC50 = 8nM,Dmax>95%).
- 通过化合物3b降解CARM1是VHL和蛋白酶体依赖和高度选择性的.
- CARM1降解导致基质甲基化的下调,并抑制了癌细胞迁移.
结论:
- CARM1 PROTACs是有效的工具,可以在细胞中实现强效和选择性的CARM1降解.
- 可以利用CARM1 PROTAC来研究CARM1的细胞功能.
- 在CARM1驱动的癌症中,CARM1 PROTAC具有作为治疗剂的潜力.
相关概念视频
02:04Co-activators and Co-repressors
7.4K
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
7.4K
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K
01:32Chromatin Modification in iPS Cells
1.7K
Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
1.7K
02:58Regulated Protein Degradation
2.6K
2.6K
02:25Spreading of Chromatin Modifications
8.3K
The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer...
Writers
The writer...
8.3K