相关实验视频

Updated: Jul 11, 2025

Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions

Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions

Published on: August 2, 2018

以结构为导向的优化N-基醇衍生抑制剂的抑制因子抑制缺氧诱导因子-α的结构导向优化

Thomas P Corner¹, Ryan Z R Teo¹, Yue Wu²

¹Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford United Kingdom lennart.brewitz@chem.ox.ac.uk christopher.schofield@chem.ox.ac.uk.

Chemical science

|November 16, 2023

概括

研究人员开发了选择性小分子抑制剂,向抑制缺氧诱导因子-α (FIH) 的抑制因子,这是缺氧反应的关键调节者. 这些基于N-西醇支架的新型化合物,通过调节缺氧诱导因子 (HIF) 信号,显示出对治疗应用的希望.

科学领域:

生物化学生物化学
分子生物学分子生物学
药用化学医学化学

背景情况:

缺氧诱导因子 (HIF) 是人类缺氧反应的中央调节者.
抑制低氧诱导因子-α (FIH) 和HIF-α prolyl残留基酶 (PHD) 是通过基化控制HIF活性的关键酶.
虽然PHD抑制剂在临床上使用,但选择性FIH抑制剂尽管具有治疗潜力,但仍未得到充分研究.

研究的目的:

探索N-西醇支架,用于开发选择性抑制二氧格酸盐 (2OG) 氧化酶的抑制剂.
发现和优化具有对FIH抑制高选择性的N-基醇衍生物,而不是其他2OG氧化酶.
研究新型FIH抑制剂的细胞效应和作用机制.

主要方法:

结构导向优化N-西醇衍生物.
生物物理测试以确定酶抑制常量 (Ki) 和选择性.
细胞测试以评估FIH依赖基因表达和脂质积累的调制.
射线晶体学以阐明抑制剂结合模式.

主要成果:

N-西醇支架成功调整为选择性FIH抑制.
优化的衍生体显示出FIH对PHD2和其他2OG氧化酶 (例如Jmjd5,ASβH,KDM4A) 的显著选择性.
FIH抑制剂调节了FIH依赖基因表达,并减少了脂肪细胞中的脂质积累.
结晶学数据显示,FIH活性部位的抑制剂与2OG和基质具有竞争性结合.

结论:

N-西醇衍生物代表了一类有前途的选择性FIH抑制剂.
这些抑制剂具有调节低氧反应和相关代谢过程的潜力.
可以进一步衍生N-西醇支架,用于选择性抑制其他2OG氧化酶.

更多相关视频

Induction and Testing of Hypoxia in Cell Culture

Induction and Testing of Hypoxia in Cell Culture

Published on: August 12, 2011

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

相关概念视频

Regulation of Angiogenesis and Blood Supply

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...

Cancer Therapies

Cancer Therapies

Cancer therapies are various modes of treatment, such as surgery, radiation therapy, and chemotherapy that are administered to cancer patients.
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...