作为潜在的Bcr-Abl/C-Src双酶抑制剂优化策略,与保持抗瘤活性一起,破坏了与烯基基组的向结合
Ching Lin1, Hsin-Yi Chiang1, Grace Shiahuy Chen2
1National Taiwan University, School of Pharmacy, College of Medicine, Taipei 100 Taiwan.
Bioorganic & medicinal chemistry letters
|January 15, 2025
概括
研究人员优化了慢性髓性白血病 (CML) 的双酶抑制剂,以减少副作用. 一种新的化合物保持了抗癌作用,尽管目标抑制较弱,这表明了更安全的CML治疗的新策略.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 计算化学的计算化学
背景情况:
- 目前用于慢性髓性白血病 (CML) 的治疗方法通常会导致显著的副作用.
- 准Bcr-Abl和C-Src激酶是CML治疗的验证策略.
- 需要使用更好的安全性配置文件的CML疗法.
研究的目的:
- 为了计算优化一个Bcr-Abl/C-Src双酶抑制剂.
- 为了研究干-标结合和毒性之间的关系.
- 开发一种新的CML治疗方法,减少副作用,同时保持有效性.
主要方法:
- 计算机辅助药物设计和优化.
- 新型激酶抑制剂的合成和表征.
- 在体外生化测试以确定激酶抑制常量 (IC50).
- 基于细胞的抗扩散试验.
主要成果:
- 与博苏替尼相比,化合物21b对Bcr-Abl/C-Src的抑制明显较弱 (∼1000倍).
- 化合物21b在细胞分析中表现出与博苏替尼比拟的抗扩散活性.
- 引入一种烯基组被确定为维持抗瘤活性的关键修改.
- 假设改变的结合相互作用有助于改善毒性概况.
结论:
- 计算优化策略成功识别了一种具有潜在改善毒性概况的双酶抑制剂.
- 烯基基组可以成为设计强效和更安全的CML治疗方法的有价值部分.
- 破坏的带-标结合可能是一个可行的方法,以减轻酶抑制剂的非标毒性.
- 需要进一步的研究来确认化合物21b的降低毒性和临床疗效.
相关概念视频
02:57Targeted Cancer Therapies
7.4K
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...
7.4K
02:50Combination Therapies and Personalized Medicine
4.8K
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...
4.8K
02:34Inhibition of Cdk Activity
4.6K
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...
4.6K
02:56Treatment Resistant Cancers
3.2K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.2K
01:27Transducer Mechanism: Enzyme-Linked Receptors
2.3K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.3K
01:26Targets for Drug Action: Overview
6.0K
Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
6.0K