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

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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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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
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)
skos:prefLabel	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/predkladatel	Přírodovědecká fakulta
http://linked.open...avai/riv/aktivita	N
http://linked.open...avai/riv/aktivity	N
http://linked.open...iv/cisloPeriodika	4
http://linked.open...vai/riv/dodaniDat	2012
http://linked.open...aciTvurceVysledku	Paruch, Kamil
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Masarykova univerzita / Přírodovědecká fakulta
http://linked.open...dnocenehoVysledku	234219
http://linked.open...ai/riv/idVysledku	RIV/00216224:14310/11:00055930
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	kinase 1 (CHK1) activity inhibitor (en)
http://linked.open.../riv/klicoveSlovo	kinase 1 (CHK1) activity inhibitor
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	CC
http://linked.open...ichTvurcuVysledku	1 (xsd:int)
http://linked.open...cetTvurcuVysledku	17 (xsd:int)
http://linked.open...UplatneniVysledku	2011
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	12 (xsd:int)
http://bibframe.org/vocab/doi	10.1158/1535-7163.MCT-10-0928
http://localhost/t...ganizacniJednotka	14310
is http://linked.open...avai/riv/vysledek of	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

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