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Related Concept Videos

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...

M-Cdk Drives Transition Into Mitosis

M-Cdk Drives Transition Into Mitosis

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...

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Related Experiment Video

Updated: Jun 4, 2025

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

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Published on: October 26, 2015

Identification of a Potent CDK8 Inhibitor Using Structure-Based Virtual Screening.

Tony Eight Lin^1,2, Ching-Hsuan Chou³, Yi-Wen Wu¹

¹Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

Journal of Chemical Information and Modeling

|December 31, 2024

Summary

Researchers identified a novel compound, P162-0948, that inhibits Cyclin-dependent kinase 8 (CDK8). This CDK8 inhibitor shows potential for treating pulmonary fibrosis by reducing cell migration and blocking key signaling pathways involved in lung scarring.

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Last Updated: Jun 4, 2025

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

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Published on: October 26, 2015

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Published on: May 3, 2018

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

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Published on: January 22, 2019

Area of Science:

Biochemistry
Pharmacology
Cell Biology

Background:

Pulmonary fibrosis involves excessive lung tissue scarring, often linked to Transforming Growth Factor-beta (TGF-β) signaling.
TGF-β induces epithelial-to-mesenchymal transition (EMT) and epithelial cell migration, contributing to fibrosis.
Cyclin-dependent kinase 8 (CDK8) mediates TGF-β pathways, presenting a potential therapeutic target for pulmonary fibrosis.

Purpose of the Study:

To identify novel inhibitors of CDK8 through structure-based virtual screening.
To characterize the inhibitory activity, selectivity, and structural novelty of identified compounds.
To evaluate the therapeutic potential of a novel CDK8 inhibitor in preclinical models of pulmonary fibrosis.

Main Methods:

Performed structure-based virtual screening of 1.6 million compounds to identify CDK8 inhibitors.
Characterized the identified inhibitor P162-0948 for its inhibitory concentration (IC50) and kinase selectivity.
Assessed the effects of P162-0948 on A549 human alveolar epithelial cells, focusing on cell migration and EMT markers.

Main Results:

Identified a novel, potent CDK8 inhibitor, P162-0948, with an IC50 of 50.4 nM.
P162-0948 demonstrated selectivity for CDK8 over 60 other kinases and possesses a unique chemical structure.
In A549 cells, P162-0948 reduced cell migration, EMT protein expression, and nuclear Smad phosphorylation, indicating TGF-β/Smad pathway disruption.

Conclusions:

P162-0948 is a potent and structurally novel inhibitor of CDK8.
The compound effectively inhibits key cellular processes implicated in pulmonary fibrosis.
P162-0948 represents a promising lead compound for developing new therapeutics for pulmonary fibrosis.