About: Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening     Goto   Sponge   NotDistinct   Permalink

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Description
  • Checkpoint kinase 1 (CHK1) is an essential serine/threonine kinase that responds to DNA damage and stalled DNA replication. CHK1 is essential for maintenance of replication fork viability during exposure to DNA antimetabolites. In human tumor cell lines, ablation of CHK1 function during antimetabolite exposure led to accumulation of double-strand DNA breaks and cell death. Here, we extend these observations and confirm ablation of CHK2 does not contribute to these phenotypes and may diminish them. Furthermore, concomitant suppression of cyclin-dependent kinase (CDK) activity is sufficient to completely antagonize the desired CHK1 ablation phenotypes. These mechanism-based observations prompted the development of a high-content, cell-based screen for g-H2AX induction, a surrogate marker for double-strandDNAbreaks. This mechanism-based functional approach was used to optimize small molecule inhibitors of CHK1.
  • Checkpoint kinase 1 (CHK1) is an essential serine/threonine kinase that responds to DNA damage and stalled DNA replication. CHK1 is essential for maintenance of replication fork viability during exposure to DNA antimetabolites. In human tumor cell lines, ablation of CHK1 function during antimetabolite exposure led to accumulation of double-strand DNA breaks and cell death. Here, we extend these observations and confirm ablation of CHK2 does not contribute to these phenotypes and may diminish them. Furthermore, concomitant suppression of cyclin-dependent kinase (CDK) activity is sufficient to completely antagonize the desired CHK1 ablation phenotypes. These mechanism-based observations prompted the development of a high-content, cell-based screen for g-H2AX induction, a surrogate marker for double-strandDNAbreaks. This mechanism-based functional approach was used to optimize small molecule inhibitors of CHK1. (en)
Title
  • Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening
  • Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening (en)
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  • Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening
  • Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening (en)
skos:notation
  • RIV/00216224:14310/11:00055930!RIV12-MSM-14310___
http://linked.open...avai/riv/aktivita
http://linked.open...avai/riv/aktivity
  • N
http://linked.open...iv/cisloPeriodika
  • 4
http://linked.open...vai/riv/dodaniDat
http://linked.open...aciTvurceVysledku
http://linked.open.../riv/druhVysledku
http://linked.open...iv/duvernostUdaju
http://linked.open...titaPredkladatele
http://linked.open...dnocenehoVysledku
  • 234219
http://linked.open...ai/riv/idVysledku
  • RIV/00216224:14310/11:00055930
http://linked.open...riv/jazykVysledku
http://linked.open.../riv/klicovaSlova
  • kinase 1 (CHK1) activity inhibitor (en)
http://linked.open.../riv/klicoveSlovo
http://linked.open...odStatuVydavatele
  • US - Spojené státy americké
http://linked.open...ontrolniKodProRIV
  • [D2164B02B392]
http://linked.open...i/riv/nazevZdroje
  • Molecular Cancer Therapeutics
http://linked.open...in/vavai/riv/obor
http://linked.open...ichTvurcuVysledku
http://linked.open...cetTvurcuVysledku
http://linked.open...UplatneniVysledku
http://linked.open...v/svazekPeriodika
  • 10
http://linked.open...iv/tvurceVysledku
  • Davis, Nicole
  • Labroli, Marc
  • Parry, David
  • Paruch, Kamil
  • Seghezzi, Wolfgang
  • Wiswell, Derek
  • Bhagwat, Bhagyashree
  • Dwyer, Michael P.
  • Gu, Danling
  • Guzi, Timothy J.
  • Hsieh, Yunsheng
  • Lee, Suining
  • Liu, Ming
  • Penaflor, Ervin
  • Shanahan, Frances
  • Taricani, Lorena
  • Wang, Wei
issn
  • 1535-7163
number of pages
http://bibframe.org/vocab/doi
  • 10.1158/1535-7163.MCT-10-0928
http://localhost/t...ganizacniJednotka
  • 14310
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