Abstract
Chemo- and radiotherapies that target DNA are the mainstay of cancer treatment. In response to DNA damage, cells are arrested in multiple checkpoints in the cell cycle to allow the damaged DNA to be repaired before progressing into mitosis. Normal cells are arrested in the G1 phase mediated by the p53 tumor suppressor, and p53-deficient cancer cells are arrested in the S or G2 phase. Checkpoint kinase 1 (Chk 1) is a serine / threonine protein kinase and a key mediator in the DNA damage-induced checkpoint network. When the G2 or S checkpoint is abrogated by the inhibition of Chk1, p53-deficient cancer cells undergo mitotic catastrophe and eventually apoptosis, whereas normal cells are still arrested in the G1 phase. Thus, Chk1 inhibitors can preferentially potentiate the efficacy of DNA damaging agents in cancer cells, and Chk1 is an attractive therapeutic target for cancer treatment, especially since approximately 50% of all human cancers are p53-deficient. This review discusses the rationale of Chk1 as an anticancer target, the structural basis for designing Chk1 inhibitors, and recently disclosed Chk1 inhibitors.
Keywords: Chk1 inhibitor, Anticancer agent, DNA-damaging agent, Adjuvant therapy, DNA damage, Cell cycle, checkpoint, Kinase, Singnal transduction
Anti-Cancer Agents in Medicinal Chemistry
Title: Chk1 Inhibitors for Novel Cancer Treatment
Volume: 6 Issue: 4
Author(s): Zhi-Fu Tao and Nan-Horng Lin
Affiliation:
Keywords: Chk1 inhibitor, Anticancer agent, DNA-damaging agent, Adjuvant therapy, DNA damage, Cell cycle, checkpoint, Kinase, Singnal transduction
Abstract: Chemo- and radiotherapies that target DNA are the mainstay of cancer treatment. In response to DNA damage, cells are arrested in multiple checkpoints in the cell cycle to allow the damaged DNA to be repaired before progressing into mitosis. Normal cells are arrested in the G1 phase mediated by the p53 tumor suppressor, and p53-deficient cancer cells are arrested in the S or G2 phase. Checkpoint kinase 1 (Chk 1) is a serine / threonine protein kinase and a key mediator in the DNA damage-induced checkpoint network. When the G2 or S checkpoint is abrogated by the inhibition of Chk1, p53-deficient cancer cells undergo mitotic catastrophe and eventually apoptosis, whereas normal cells are still arrested in the G1 phase. Thus, Chk1 inhibitors can preferentially potentiate the efficacy of DNA damaging agents in cancer cells, and Chk1 is an attractive therapeutic target for cancer treatment, especially since approximately 50% of all human cancers are p53-deficient. This review discusses the rationale of Chk1 as an anticancer target, the structural basis for designing Chk1 inhibitors, and recently disclosed Chk1 inhibitors.
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Cite this article as:
Tao Zhi-Fu and Lin Nan-Horng, Chk1 Inhibitors for Novel Cancer Treatment, Anti-Cancer Agents in Medicinal Chemistry 2006; 6 (4) . https://dx.doi.org/10.2174/187152006777698132
DOI https://dx.doi.org/10.2174/187152006777698132 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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