Related Experiment Video

Updated: Jan 31, 2026

Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells
09:51

Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells

Published on: June 30, 2023

1.5K

A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations

Luis I Toledo1, Matilde Murga, Rafal Zur

  • 1Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.

Nature Structural & Molecular Biology
|May 10, 2011
PubMed

Insights

Researchers identified potent ATR inhibitors using a cell-based screen. ATR inhibition causes DNA damage and is toxic to p53-deficient cells, especially with replication stress. NVP-BEZ235 shows broad kinase inhibition.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Oncogene activation induces replication stress, a type of DNA damage.
  • The ATM and Rad3-related (ATR) kinase is a key responder to replicative stress.
  • A lack of potent ATR inhibitors has limited research in this area.

Purpose of the Study:

  • To develop a cell-based screening strategy to identify ATR inhibitors.
  • To investigate the effects of ATR inhibition on DNA damage and cell toxicity.
  • To characterize novel ATR inhibitors, including their activity against other kinases.

Main Methods:

  • A cell-based screening assay was employed to identify compounds with ATR inhibitory activity.
  • The effects of ATR inhibition on chromosomal breakage were assessed under conditions that stall replication forks.
  • Cellular toxicity of ATR inhibition was evaluated in p53-deficient cells, particularly when combined with replicative stress conditions.

Main Results:

  • A screening strategy successfully identified compounds with nanomolar ATR inhibitory activity.
  • Pharmacological ATR inhibition leads to replicative stress and chromosomal breakage.
  • ATR inhibition exhibits significant toxicity in p53-deficient cells, exacerbated by conditions like cyclin E overexpression.
  • NVP-BEZ235, a PI3K/mTOR inhibitor, was identified as a potent inhibitor of ATM, ATR, and DNA-PKcs.

Conclusions:

  • A novel screening approach effectively identified potent ATR inhibitors.
  • ATR inhibition is a promising strategy for targeting cancer, especially in p53-deficient contexts.
  • NVP-BEZ235 possesses broad kinase inhibitory activity, including against ATR, suggesting potential for multi-targeted cancer therapy.

More Related Videos

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions07:40

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions

Published on: May 27, 2021

4.6K
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

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

Published on: December 7, 2014

15.3K

Related Concept Videos

Cancers Originate from Somatic Mutations in a Single Cell02:21

Cancers Originate from Somatic Mutations in a Single Cell

Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
14.9K
Mutations01:39

Mutations

Overview
94.5K
Mutations01:35

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
44.5K
Lethal Alleles02:41

Lethal Alleles

Agouti: A Lethal Allele
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
18.0K
Viral Mutations00:36

Viral Mutations

A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
39.9K
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.0K