利用酶背囊中的结构变异性来调节TAM抑制剂的多药理学
Megan D Hopkins1, Dehui Zhang1, Zhilong Chen1
1Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
European journal of medicinal chemistry
|April 4, 2025
概括
研究人员开发了针对TAM激酶的新型小分子抑制剂,这些激酶在癌症和免疫系统中至关重要. 化合物,UNC8212,显示强烈的活性和有利的药理动力学,为向癌症治疗提供了潜力.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 药用化学 医学化学
背景情况:
- TAM激酶 (Tyro3,Axl,Mer) 在瘤进展和先天免疫反应中都起着复杂的作用.
- 这些激酶具有部分冗余但特定于环境的功能,需要选择性抑制策略来获得治疗益处.
- 向TAM激酶为癌症治疗提供了一个有希望的途径,特别是在调节瘤微环境和免疫逃避方面.
研究的目的:
- 发现新的小分子抑制剂,具有不同的选择性概况,向TAM激酶家族.
- 通过利用 TAM 激酶背口袋的独特结构特征来调节抑制剂的多药理学.
- 为了确定一种具有强大的TAM激酶抑制活性和有利的药物样性质的化合物.
主要方法:
- 基于结构的药物设计和药物化学方法被用于开发小分子抑制剂.
- 多药学调制是通过准多元化的TAM激酶的背囊来实现的.
- 通过使用NanoBRET和基于细胞的测试来验证目标参与.
- 在静脉和腹腔内给药后评估了药物动力学特性.
主要成果:
- 发现了几种小分子抑制剂,它们对TAM激酶具有明显的选择性概况.
- 该化合物被指定为45 (UNC8212),对整个TAM激酶家族表现出强大的抑制活性.
- 纳米BRET和基于细胞的测定证实了化合物45的目标接触.
- 化合物45在体内表现出有利的药理动力学特征.
结论:
- 成功开发了针对TAM激酶的新型小分子抑制剂,为癌症治疗提供了潜力.
- 化合物UNC8212表现出强大且广泛的TAM激酶抑制,具有有前途的药理动力学特性.
- 这项研究为开发向疗法提供了基础,该疗法可调节各种癌症类型的TAM激酶信号传递.
相关概念视频
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
01:22Amplifying Signals via Enzymatic Cascade
8.2K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.2K
01:26Receptor Tyrosine Kinases
11.9K
Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
11.9K
01:58Cooperative Allosteric Transitions
7.8K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
7.8K
01:08Allosteric Regulation
57.2K
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
57.2K
01:26Targets for Drug Action: Overview
5.9K
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...
5.9K