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Cancer Res DOI:10.1158/0008-5472.CAN-14-2650

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

Publication TypeJournal Article
Year of Publication2014
AuthorsKawasumi, M, Bradner, JE, Tolliday, N, Thibodeau, R, Sloan, H, Brummond, KM, Nghiem, P
JournalCancer Res
Volume74
Issue24
Pages7534-45
Date Published2014 Dec 15
ISSN1538-7445
KeywordsAtaxia Telangiectasia Mutated Proteins, Catalysis, Cell Line, Tumor, Cell Survival, Checkpoint Kinase 1, DNA Damage, G2 Phase Cell Cycle Checkpoints, HeLa Cells, Humans, Neoplasms, Protein Kinases, Signal Transduction, Small Molecule Libraries, Tumor Suppressor Protein p53
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.

DOI10.1158/0008-5472.CAN-14-2650
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25336189?dopt=Abstract

Alternate JournalCancer Res.
PubMed ID25336189
PubMed Central IDPMC4268153
Grant ListR01 AR049832 / AR / NIAMS NIH HHS / United States
R01-AR049832 / AR / NIAMS NIH HHS / United States