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Cancer Res. 2014 Dec 15;74(24):7534-45. doi: 10.1158/0008-5472.CAN-14-2650. Epub 2014 Oct 21.

Identification of ATR-Chk1 pathway inhibitors that selectively target p53-deficient cells without directly suppressing ATR catalytic activity.

Author information

1
Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington. kawasumi@uw.edu pnghiem@uw.edu.
2
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
3
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
4
Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
5
University of Pittsburgh Center for Chemical Methodologies and Library Development, Pittsburgh, Pennsylvania.
6
Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. kawasumi@uw.edu pnghiem@uw.edu.

Abstract

Resistance to DNA-damaging chemotherapy is a barrier to effective treatment that appears to be augmented by p53 functional deficiency in many cancers. In p53-deficient cells in which the G1-S checkpoint is compromised, cell viability after DNA damage relies upon intact intra-S and G2-M checkpoints mediated by the ATR (ataxia telangiectasia and Rad3 related) and Chk1 kinases. Thus, a logical rationale to sensitize p53-deficient cancers to DNA-damaging chemotherapy is through the use of ATP-competitive inhibitors of ATR or Chk1. To discover small molecules that may act on uncharacterized components of the ATR pathway, we performed a phenotype-based screen of 9,195 compounds for their ability to inhibit hydroxyurea-induced phosphorylation of Ser345 on Chk1, known to be a critical ATR substrate. This effort led to the identification of four small-molecule compounds, three of which were derived from known bioactive library (anthothecol, dihydrocelastryl, and erysolin) and one of which was a novel synthetic compound termed MARPIN. These compounds all inhibited ATR-selective phosphorylation and sensitized p53-deficient cancer cells to DNA-damaging agents in vitro and in vivo. Notably, these compounds did not inhibit ATR catalytic activity in vitro, unlike typical ATP-competitive inhibitors, but acted in a mechanistically distinct manner to disable ATR-Chk1 function. Our results highlight a set of novel molecular probes to further elucidate druggable mechanisms to improve cancer therapeutic responses produced by DNA-damaging drugs.

PMID:
25336189
PMCID:
PMC4268153
DOI:
10.1158/0008-5472.CAN-14-2650
[Indexed for MEDLINE]
Free PMC Article

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