全转录增强关联域棕化口袋共价抑制剂
Jinhyuk Kim1,2, Hadong Kim2, Jongwan Kim3,4
1The Interdisciplinary Graduate Program in Integrative Biotechnology & Translational Medicine, Yonsei University, Incheon 21983, Republic of Korea.
Journal of medicinal chemistry
|November 2, 2024
概括
研究人员开发了一种针对Hippo-TEAD通路的新药,用于治疗癌症. 化合物3是一种强大的,可口服的TEAD蛋白的抑制剂,提供了一个有前途的治疗策略.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 药物发现 药物发现 药物发现
背景情况:
- 河马信号通路调节器官大小,并与癌症有关.
- 转录增强关联域 (TEAD) 蛋白质是该途径的关键调解者.
- TEAD蛋白的棕化对其致癌活性至关重要,使其成为治疗点.
研究的目的:
- 开发针对TEAD棕化位点的新型抑制剂.
- 为了确定癌症治疗的强效和口服生物可用共价泛-TEAD抑制剂.
主要方法:
- 基于结构的药物设计,利用K-975.5的见解.
- 代优化热点化合物,以增强功效和药理动力学特性.
- 对TEAD蛋白质的抑制活性评估.
主要成果:
- 化合物1被确定为通过基于结构的设计的初步打击.
- 优化导致了化合物3的开发,一种强大的共价泛TEAD抑制剂.
- 化合物3显示出高强度和良好的口服生物可用性.
结论:
- 向TEAD棕化是一种可行的策略,用于治疗TEAD依赖性癌症.
- 化合物3代表了在瘤学中进一步发展的有希望的候选药物.
- 开发的抑制剂有效向多个TEAD蛋白,提供广泛的治疗潜力.
相关概念视频
Phosphoinositides and PIPs
8.5K
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
8.5K
Covalently 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
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
Lipids as Anchors
5.5K
In the plasma membrane, the lipids forming the bilayer can also act as an anchor to tether proteins to the membrane. The three main types of lipid anchors found in eukaryotes are – prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol or GPI groups. Prenyl and fatty acyl groups act as anchors on the cytosolic surface of the membrane, whereas GPI anchors proteins on the extracellular side.
The carboxy-terminal of most of the prenylated proteins, such as Ras proteins, contains...
The carboxy-terminal of most of the prenylated proteins, such as Ras proteins, contains...
5.5K
cAMP-dependent Protein Kinase Pathways
6.1K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
6.1K
Pinching-off of Coated Vesicles
3.1K
Vesicle budding is orchestrated by distinct cytosolic proteins such as adaptor proteins, coat proteins, and GTPases. To initiate vesicle budding, membrane-bending proteins containing crescent-shaped BAR domains bind to the lipid heads in the bilayer and distort the membrane to form a protein-coated vesicle bud. Adaptors proteins such as AP2 for clathrin-coated vesicles can nucleate on the deformed membrane. Finally, coat proteins such as clathrin or COPI and COPII assemble into a coat forming...
3.1K


