Related Experiment Video

Updated: Dec 17, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

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

11.7K

Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors

Sonia Martínez-González1, Ana Belén García1, M Isabel Albarrán1

  • 1Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro 3, E-28029, Madrid, Spain.

European Journal of Medicinal Chemistry
|June 30, 2020
PubMed

Insights

Researchers developed novel pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as potential CDK8 inhibitors for cancer therapy. Compound 2 demonstrated potent CDK8 inhibition (IC50 = 8.25 nM) and selectivity, offering a new therapeutic avenue.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • Cyclin-dependent kinase 8 (CDK8) is implicated in oncogenic pathways and frequently overexpressed in cancers.
  • CDK8's role in transcriptional regulation makes it a promising target for cancer therapeutics.
  • Targeting CDK8 offers a potential strategy for novel cancer treatments.

Purpose of the Study:

  • To design and synthesize novel pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as potential CDK8 inhibitors.
  • To evaluate the in vitro inhibitory activity and selectivity of these novel compounds against CDK8.
  • To explore the therapeutic potential of these compounds in cancer treatment.

Main Methods:

  • Structure-based drug design considering CDK8 P-loop flexibility.
  • Synthesis of tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives.
  • In vitro kinase inhibition assays, co-crystal studies, and cellular assays measuring STAT1 phosphorylation.

Main Results:

  • Identified compound 2 as the most potent inhibitor with an IC50 of 8.25 nM against CDK8.
  • Compound 2 exhibited a remarkable selectivity profile.
  • Compound 2 demonstrated moderate reduction of CDK8 substrate STAT1 phosphorylation in cellular models.

Conclusions:

  • The novel pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives represent a promising chemical series for CDK8 inhibitor development.
  • Compound 2 is a potent and selective CDK8 inhibitor with potential therapeutic applications in oncology.
  • This study provides an alternative strategy for discovering potential therapeutic agents targeting CDK8.
Keywords:
CDK8P-loop flexibilitySelectivityType II inhibitorspyrido[2,3-b][1,5]benzoxazepin-5(6H)-one scaffold

More Related Videos

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay05:17

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

Published on: February 9, 2021

1.9K
Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions07:12

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

Published on: July 17, 2020

6.6K

Related Concept Videos

Inhibition of Cdk Activity02:34

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...
5.4K
M-Cdk Drives Transition Into Mitosis02:15

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...
6.1K
Positive Regulator Molecules02:39

Positive Regulator Molecules

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.
6.4K
Aromatic Hydrocarbon Cations: Structural Overview01:18

Aromatic Hydrocarbon Cations: Structural Overview

Cycloheptatriene is a neutral monocyclic unsaturated hydrocarbon that consists of an odd number of carbon atoms and an intervening sp3 carbon in the ring. The three double bonds in the ring correspond to 6 π electrons, which is a Huckel number, and therefore satisfies the criteria of 4n + 2 π electrons. However, the intervening sp3 carbon disrupts the continuous overlap of p orbitals. As a result, cycloheptatriene is not aromatic.
Removing one hydrogen from the intervening CH2 group...
3.5K
Nomenclature of Aromatic Compounds with Multiple Substituents01:11

Nomenclature of Aromatic Compounds with Multiple Substituents

When more than one substituent is present on the benzene ring, the IUPAC nomenclature depends on the number of substituents present.
For disubstituted benzene derivatives, with two groups attached to the benzene ring, three constitutional isomers are possible. For example, consider dimethyl benzene, often called xylene, where the second methyl group can be substituted at the second, third, or fourth carbon. The relative position of the substituents is represented by prefixes ortho, meta, or...
9.8K
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

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...
3.2K