精确的符合性控制产生了具有强烈抗瘤活性的高强度和特别选择性的BRD4降解剂
Jiantao Hu1, Biao Hu1, Fuming Xu1
1Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
Journal of medicinal chemistry
|June 8, 2023
概括
研究人员开发了高度选择性的BRD4蛋白质降解剂BD-7148和BD-9136,使用精确的形状控制. 这些化合物有效地抑制瘤生长,表明BRD4降解是有前途的癌症治疗策略.
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:
- 原体和外端蛋白 (BET) 蛋白质,特别是BRD4,与各种癌症有关.
- 有针对性的蛋白质降解为癌症治疗提供了一种新的治疗方法.
研究的目的:
- 使用PROTAC技术开发强效和高度选择性的BRD4降解剂.
- 在临床前模型中评估这些降解剂的疗效和选择性.
主要方法:
- 用了一个非选择性的BET抑制剂和一个cereblon连接体用于PROTAC设计.
- 采用精确的形状控制来实现目标选择性.
- 通过蛋白质组分析和体内研究评估蛋白质降解.
主要成果:
- 开发了BD-7148和BD-9136,在纳米分子度下实现了强大的BRD4降解.
- 与BRD2/BRD3.3相比,对BRD4降解的选择性超过1000倍.
- 在瘤组织中确认了选择性的BRD4衰减,在没有不良影响的小鼠中显著抑制了瘤生长.
结论:
- 选择性降解BRD4是一种可行的治疗策略,用于人类的癌症.
- 开发的PROTACs为向癌症治疗提供了一个有希望的方法.
- 这项研究为设计高度选择性的PROTAC降解剂提供了蓝图.
更多相关视频
10:44Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
13.3K
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
11.4K
相关概念视频
Targeted Cancer Therapies
7.7K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
7.7K
Inhibition of Cdk Activity
4.8K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.8K
Structure-Activity Relationships and Drug Design
800
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
800
Combination Therapies and Personalized Medicine
5.0K
Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.0K
