结构元素使EGFR突变激酶域具有下一代小分子抑制剂的特异性
Tahereh Damghani1, Florian Wittlinger2, Tyler S Beyett3
1Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, United States.
Methods in enzymology
|May 28, 2023
概括
新的EGFR抑制剂通过向C797S突变来克服耐药性. 结构分析揭示了关键的键,使得选择性结合能够抵抗表皮生长因子受体 (EGFR) 突变.
科学领域:
- 在瘤学瘤学.
- 结构生物学 结构生物学
- 药用化学 医学化学
背景情况:
- 表皮生长因子受体 (EGFR) 抑制剂对于治疗具有特定突变的癌症至关重要.
- 获得的耐药性,特别是C797S突变,限制了当前第三代EGFR抑制剂的疗效.
- 开发新型抑制剂对于克服耐药性和改善患者治疗结果至关重要.
研究的目的:
- 审查结构性特征的EGFR氨酸激酶抑制剂 (TKI).
- 确定能够抑制C797S耐药突变的分子特征.
- 了解新一代EGFR抑制剂的结合模式和相互作用.
主要方法:
- 对针对临床相关突变的结构性特征EGFRTKI进行系统审查.
- 对分子因素的分析,包括键相互作用,这些因素赋予了选择性.
- 在ATP和全位的结合模式的比较.
主要成果:
- 新一代EGFR抑制剂使用与K745和D855残留物保持一致的键.
- 结构洞察力揭示了选择性结合C797S突变EGFR的机制.
- 识别以前未充分利用的结相互作用.
结论:
- 对较新的EGFR抑制剂的结构理解为设计抗耐药突变物药物的基础.
- 针对特定的结相互作用是克服C797S介导电阻的关键.
- 进一步开发第四代抑制剂对于管理EGFR突变癌症具有前途.
相关概念视频
Mitogens and the Cell Cycle
6.6K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K
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
Transducer Mechanism: Enzyme-Linked Receptors
2.5K
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:
2.5K
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


