| GUZI, Timothy J., Kamil PARUCH, Michael P. DWYER, Marc LABROLI, Frances SHANAHAN, Nicole DAVIS, Lorena TARICANI, Derek WISWELL, Wolfgang SEGHEZZI, Ervin PENAFLOR, Bhagyashree BHAGWAT, Wei WANG, Danling GU, Yunsheng HSIEH, Suining LEE, Ming LIU a David PARRY. Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening. Molecular Cancer Therapeutics. Philadelphia: American Association for Cancer Research, 2011, roč. 10, č. 4, s. 591–602. ISSN 1535-7163. Dostupné z: https://dx.doi.org/10.1158/1535-7163. |
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@article{974260,
author = {Guzi, Timothy J. and Paruch, Kamil and Dwyer, Michael P. and Labroli, Marc and Shanahan, Frances and Davis, Nicole and Taricani, Lorena and Wiswell, Derek and Seghezzi, Wolfgang and Penaflor, Ervin and Bhagwat, Bhagyashree and Wang, Wei and Gu, Danling and Hsieh, Yunsheng and Lee, Suining and Liu, Ming and Parry, David},
article_location = {Philadelphia},
article_number = {4},
doi = {http://dx.doi.org/10.1158/1535-7163},
keywords = {kinase 1 (CHK1) activity inhibitor},
language = {eng},
issn = {1535-7163},
journal = {Molecular Cancer Therapeutics},
title = {Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening},
volume = {10},
year = {2011}
}
TY - JOUR
ID - 974260
AU - Guzi, Timothy J. - Paruch, Kamil - Dwyer, Michael P. - Labroli, Marc - Shanahan, Frances - Davis, Nicole - Taricani, Lorena - Wiswell, Derek - Seghezzi, Wolfgang - Penaflor, Ervin - Bhagwat, Bhagyashree - Wang, Wei - Gu, Danling - Hsieh, Yunsheng - Lee, Suining - Liu, Ming - Parry, David
PY - 2011
TI - Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening
JF - Molecular Cancer Therapeutics
VL - 10
IS - 4
SP - 591–602
EP - 591–602
PB - American Association for Cancer Research
SN - 15357163
KW - kinase 1 (CHK1) activity inhibitor
N2 - 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. Specifically, the assay was used to mechanistically define the optimal in-cell profile with compounds exhibiting varying degrees of CHK1, CHK2, and CDK selectivity. Using this approach, SCH 900776 was identified as a highly potent and functionally optimal CHK1 inhibitor with minimal intrinsic antagonistic properties. SCH 900776 exposure phenocopies short interfering RNA-mediated CHK1 ablation and interacts synergistically with DNA antimetabolite agents in vitro and in vivo to selectively induce dsDNA breaks and cell death in tumor cell backgrounds.
ER -
GUZI, Timothy J., Kamil PARUCH, Michael P. DWYER, Marc LABROLI, Frances SHANAHAN, Nicole DAVIS, Lorena TARICANI, Derek WISWELL, Wolfgang SEGHEZZI, Ervin PENAFLOR, Bhagyashree BHAGWAT, Wei WANG, Danling GU, Yunsheng HSIEH, Suining LEE, Ming LIU a David PARRY. Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening. \textit{Molecular Cancer Therapeutics}. Philadelphia: American Association for Cancer Research, 2011, roč.~10, č.~4, s.~591–602. ISSN~1535-7163. Dostupné z: https://dx.doi.org/10.1158/1535-7163.
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