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Pharmacol Ther. 2014 Apr;142(1):1-10. doi: 10.1016/j.pharmthera.2013.10.005. Epub 2013 Oct 15.

CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy.

Author information

1
Eli Lilly and Company, Indianapolis, IN, United States. Electronic address: mcneely_samuel_clark@lilly.com.
2
Eli Lilly and Company, Indianapolis, IN, United States.

Abstract

CHEK1 encodes the serine/threonine kinase CHK1, a central component of the DNA damage response. CHK1 regulates cell cycle checkpoints following genotoxic stress to prevent the entry of cells with damaged DNA into mitosis and coordinates various aspects of DNA repair. Accordingly, CHK1 has become a target of considerable interest in oncology. CHK1 inhibitors potentiate the efficacy of DNA-damaging chemotherapeutics by abrogating CHK1-mediated cell cycle arrest and preventing repair of damaged DNA. In addition, CHK1 inhibitors interfere with the biological role of CHK1 as a principal regulator of the cell cycle that controls the initiation of DNA replication, stabilizes replication forks, and coordinates mitosis. Since these functions of CHK1 facilitate progression through an unperturbed cell cycle, CHK1 inhibitors are being developed not only as chemopotentiators, but also as single-agent therapies. This review is intended to provide information on the current progress of CHK1 inhibitors in pre-clinical and clinical development and will focus on mechanisms of single-agent activity and potential strategies for patient tailoring and combinations with non-genotoxic agents.

KEYWORDS:

CHK1; Checkpoint kinase 1; DNA damage response; DNA replication; WEE1

[Indexed for MEDLINE]

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