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Chemical strategies for development of ATR inhibitors

Published online by Cambridge University Press:  09 May 2014

Sabin Llona-Minguez ,
Andreas Höglund ,
Sylvain A. Jacques ,
Tobias Koolmeister  and
Thomas Helleday
Sabin Llona-Minguez*
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Andreas Höglund
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Sylvain A. Jacques
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Tobias Koolmeister
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Thomas Helleday*
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
*
*Corresponding authors: Thomas Helleday and Sabin Llona-Minguez, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. E-mail: sabin.llona.minguez@scilifelab.se; thomas.helleday@scilifelab.se
*Corresponding authors: Thomas Helleday and Sabin Llona-Minguez, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. E-mail: sabin.llona.minguez@scilifelab.se; thomas.helleday@scilifelab.se
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Abstract

ATR protein kinase is one of the key players in maintaining genome integrity and coordinating of the DNA damage response and repair signalling pathways. Inhibition of ATR prevents signalling from stalled replication forks and enhances the formation of DNA damage, particularly under conditions of replication stress present in cancers. For this reason ATR/CHK1 checkpoint inhibitors can potentiate the effect of DNA cross-linking agents, as evidenced by ATR inhibitors recently entering human clinical trials. This review aims to compile the existing literature on small molecule inhibitors of ATR, both from academia and the pharmaceutical industry, and will provide the reader with a comprehensive summary of this promising oncology target.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 16 , 2014 , e10
Copyright
Copyright © Cambridge University Press 2014 

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