基于结构的设计和特征的高强度和选择性的共价抑制剂向氨酸甲基转移酶G9a/GLP
Zongbo Feng1,2, Chunju Yang1, Yi Zhang1
1Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Journal of medicinal chemistry
|June 2, 2023
概括
一种新的共价抑制剂,化合物27,有效地向涉及癌症的G9a/GLP酶. 这种强效的候选药物在临床前模型中显示出显著的抗瘤活性和安全性.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 蛋白质氨酸甲基转移酶G9a和GLP通过基因素和非基因素甲基化调节基因表达.
- G9a和GLP的失调与各种癌症的发展和进展有关.
研究的目的:
- 发现和描述G9a/GLP的强效和选择性共价抑制剂.
主要方法:
- 使用基于结构的药物设计,结构-活性关系探索和细胞分析.
- 质谱和冲洗实验证实了共价抑制机制.
- 进行了体外增殖和殖民地形成测试,以及体内异种移植研究.
主要成果:
- 化合物27被确定为G9a/GLP的高强度和选择性共价抑制剂.
- 化合物27与非共价抑制剂相比,对癌细胞增殖和殖民地形成有较强的抑制作用.
- 在PANC-1异种移植小鼠模型中观察到显著的瘤生长抑制和良好的安全性.
结论:
- 化合物27代表了由G9a/GLP失调驱动的癌症的有前途的治疗药物.
- 共价抑制策略为向G9a/GLP在癌症治疗中提供了一种强有力的方法.
相关概念视频
02:04Covalently Linked Protein Regulators
6.9K
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....
6.9K
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K