Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor

Summary Interference with DNA damage checkpoints has been demonstrated preclinically to be a highly effective means of increasing the cytotoxicity of a number of DNA-damaging cancer therapies. Cell cycle arrest at these checkpoints protects injured cells from apoptotic cell death until DNA damage ca...

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Bibliographic Details
Published in:Investigational new drugs 2014-04, Vol.32 (2), p.213-226
Main Authors: King, Constance, Diaz, Henry, Barnard, Darlene, Barda, David, Clawson, David, Blosser, Wayne, Cox, Karen, Guo, Sherry, Marshall, Mark
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Cancer therapies
Cell cycle
Cell Cycle Checkpoints - drug effects
Cell death
Cell Line, Tumor
Checkpoint Kinase 1
Colorectal cancer
Cytotoxicity
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
DNA Damage
Doxorubicin - pharmacology
Female
Humans
Inhibitor drugs
Kinases
Lung cancer
Medicine
Medicine & Public Health
Membranes
Mice
Mice, Nude
Neoplasms - drug therapy
Neoplasms - metabolism
Oncology
Pharmaceutical sciences
Pharmacology/Toxicology
Phenylurea Compounds - pharmacology
Phenylurea Compounds - therapeutic use
Phosphorylation
Preclinical Studies
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Protein Kinases - metabolism
Proteins
Pyrazines - pharmacology
Pyrazines - therapeutic use
Studies
Tumor Suppressor Protein p53 - genetics
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Summary:Summary Interference with DNA damage checkpoints has been demonstrated preclinically to be a highly effective means of increasing the cytotoxicity of a number of DNA-damaging cancer therapies. Cell cycle arrest at these checkpoints protects injured cells from apoptotic cell death until DNA damage can be repaired. In the absence of functioning DNA damage checkpoints, cells with damaged DNA may proceed into premature mitosis followed by cell death. A key protein kinase involved in activating and maintaining the S and G2/M checkpoints is Chk1. Pharmacological inhibition of Chk1 in the absence of p53 functionality leads to abrogation of DNA damage checkpoints and has been shown preclinically to enhance the activity of many standard of care chemotherapeutic agents. LY2603618 is a potent and selective small molecule inhibitor of Chk1 protein kinase activity in vitro (IC 50  = 7 nM) and the first selective Chk1 inhibitor to enter clinical cancer trials. Treatment of cells with LY2603618 produced a cellular phenotype similar to that reported for depletion of Chk1 by RNAi. Inhibition of intracellular Chk1 by LY2603618 results in impaired DNA synthesis, elevated H2A.X phosphorylation indicative of DNA damage and premature entry into mitosis. When HeLa cells were exposed to doxorubicin to induce a G2/M checkpoint arrest, subsequent treatment with LY2603618 released the checkpoint, resulting in cells entering into metaphase with poorly condensed chromosomes. Consistent with abrogation of the Chk1 and p53-dependent G2/M checkpoint, mutant TP53 HT-29 colon cancer cells were more sensitive to gemcitabine when also treated with LY2603618, while wild-type TP53 HCT116 cells were not sensitized by LY2603618 to gemcitabine. Treatment of Calu-6 human mutant TP53 lung cancer cell xenografts with gemcitabine resulted in a stimulation of Chk1 kinase activity that was inhibited by co-administration of LY2603618. By all criteria, LY2603618 is a highly effective inhibitor of multiple aspects of Chk1 biology.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-013-0036-7