对于cyclin K分子降解剂的设计原则
Zuzanna Kozicka1,2, Dakota J Suchyta1,3, Vivian Focht1
1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Nature chemical biology
|September 7, 2023
概括
分子剂通过将其与E3结合酶结合而降解环林K. 这项研究揭示了关键的结合相互作用,并表明这些降解剂具有独特的治疗潜力,与激酶抑制剂不同.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 分子降解剂是一个有前途的治疗策略.
- 对分子的设计原理仍然不太了解.
- 现有的粘合剂通过将CDK12-cyclin K与DDB1-CUL4-RBX1 E3结合酶结合来耗尽环林K.
研究的目的:
- 研究各种小分子诱导环林K降解的机制.
- 为合理的分子设计建立一个概念框架.
- 探索环林K降解剂的治疗潜力.
主要方法:
- 通过结构,生物物理和细胞研究对91种候选降解剂的评估.
- 结构与活动关系分析.
- 对转录签名的评估.
主要成果:
- 所有评估的分子剂都需要同时与CDK12结合,并与DDB1界面残留物 (特别是Arg928) 进行激活.
- 之前识别的激酶抑制剂作为"隐秘"降解剂起作用.
- 这些的活性是可调节的,不需要强大的抑制性质.
- 与CDK12抑制剂相比,环林K降解剂表现出不同的转录特征.
结论:
- 同时结合CDK12和DDB1对于分子粘活性至关重要.
- 分子提供独特的治疗途径,与传统的激酶抑制分开.
- 这项工作为新型分子粘剂的合理设计提供了基础.
更多相关视频
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
11.4K
05:33High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
9.7K
相关概念视频
Anaphase Promoting Complex
2.9K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.9K
Positive Regulator Molecules
5.5K
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
5.5K
M-Cdk Drives Transition Into Mitosis
5.6K
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.6K
Inhibition of Cdk Activity
4.8K
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...
4.8K
Separation of Sister Chromatids
3.7K
At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...
At the onset of anaphase, separase, a proteolytic enzyme, is...
3.7K
The Cell Cycle Control System
3.0K
The cell cycle regulation directs how a cell proceeds from one phase to the next and begins mitosis. The cell cycle control system includes intracellular regulatory molecules and external triggers. They provide "stop" or "advance" signals and operate at specific cell cycle stages termed checkpoints to ensure that a particular process is completed before the cell advances to the next phase.
Cyclins and cyclin-dependent kinases (Cdks) are the primary cell cycle regulators and...
Cyclins and cyclin-dependent kinases (Cdks) are the primary cell cycle regulators and...
3.0K
