相关实验视频

Updated: Jun 12, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

计算驱动的发现一种BCR-ABL1激酶抑制剂在多抗药性慢性髓性白血病中具有活性

Jarvis Hill^1,2, R Houston Givhan^2,3, Bin Yi¹

¹Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West Green Street, Athens, Georgia 30602, United States.

Journal of medicinal chemistry

|September 23, 2024

概括

研究人员优化了激酶抑制剂,以克服由透性糖蛋白 (P-gp) 介导的多药性耐药性 (MDR). 一种新型的双cSRC/BCR-ABL1抑制剂显示P-gp流量减少和抗性白血病细胞中的强活性.

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.
分子生物学分子生物学

背景情况:

由ABCB1基因编码的透性糖蛋白 (P-gp) 是多药耐药性 (MDR) 的关键因素.
P-gp 排泄物降低了许多治疗药物的细胞内度,包括用于费城染色体阳性 (Ph+) 白血病的BCR-ABL1激酶抑制剂.
了解对P-gp流量的替代效应对于开发有效的癌症疗法至关重要.

研究的目的:

为了研究4-anilinoquinazolines和4-anilinoquinoline-3-carbonitrile激酶抑制剂在P-gp介导流量上的替代效应的影响.
为了确定具有减少P-gp流量和强大的抗白血病活性的新型激酶抑制剂.
探索用于最大限度地减少P-gp流出的计算策略.

主要方法:

综合的理论和实验方法来分析替代物效应.
新型激酶抑制剂的设计和合成.
使用基于细胞的试验评估P-gp介导的流量比率.
在Ph+和MDR-Ph+白血病细胞系 (K562和K562/Dox) 中评估化合物活性.
分子双极和pKa的计算优化.

主要成果:

鉴定一种含有基胺的双重cSRC/BCR-ABL1激酶抑制剂 (16a).
化合物16a显示显著降低了P-gp介导的流量比率.
16a对Ph+白血病细胞 (K562) 和过度表达P-gp的MDR-Ph+白血病细胞 (K562/Dox) 呈现强烈活性.
分子双极和/或pKa的计算优化有效地减少了P-gp流量.

结论:

酶抑制剂中的替代剂修饰可以有效调节P-gp介导的流量.
已确定的双抑制剂16a代表了治疗MDR Ph+白血病的有希望的候选者.
计算方法是设计具有减少P-gp流量药物的宝贵工具,提供了超越分子内键的策略.

更多相关视频

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Published on: June 17, 2022

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Published on: January 7, 2019

相关概念视频

Combination Therapies and Personalized Medicine

Combination Therapies and Personalized Medicine

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...

Targeted Cancer Therapies

Targeted Cancer Therapies

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...

Inhibition of Cdk Activity

Inhibition of Cdk Activity

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...