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Review
. 2010 Apr 28;3(5):1311-1334.
doi: 10.3390/ph3051311.

Prospects for the Use of ATR Inhibitors to Treat Cancer

Jill M Wagner  1 , Scott H Kaufmann  2
Affiliations
Review

Prospects for the Use of ATR Inhibitors to Treat Cancer

Jill M Wagner et al. Pharmaceuticals (Basel). .

Abstract

ATR is an apical kinase in one of the DNA-damage induced checkpoint pathways. Despite the development of inhibitors of kinases structurally related to ATR, as well as inhibitors of the ATR substrate Chk1, no ATR inhibitors have yet been developed. Here we review the effects of ATR downregulation in cancer cells and discuss the potential for development of ATR inhibitors for clinical use.

Keywords: ATM; ATR; Chk1; Replication checkpoint; chemotherapy.

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Figures

Figure 1
Figure 1
Structural domains of ATR in comparison to other PIKK family members. The shaded domains share the highest degree of sequence homology. ATRIP (ATR-interacting protein), FAT (FRAP, ATM, TRRAP), PRD (PIK regulatory domain), FATC (FAT domain at the carboxyl terminus).
Figure 2
Figure 2
ATM and ATR signaling pathways. DNA DSBs generally activate ATM, which along with the Mre11-Rad50-NBS1 complex, can facilitate DNA repair or phosphorylate the Chk2 kinase leading to activation of p53 followed by G1 arrest or apoptosis. Alternatively, extensive regions of single-stranded DNA that result from the continued activity of helicases after replication forks are stalled (see Figure 3) activate the ATR pathway. ATR, together with the Rad9-Hus1-Rad1 complex can activate Chk1. Chk1 in turn phosphorylates Cdc25A and Cdc25C, which targets the former for degradation and the latter for sequestration, causing the cells to arrest in S or G2. Chk1 activation can also facilitate DNA repair.
Figure 3
Figure 3
Model of the activation of ATR through Rad9 and TopBP1. See text for details. Modified from [27].
Figure 4
Figure 4
Chk1 mediates ATR-induced cell cycle arrest. ATR activates Chk1, which then phosphorylates and inactivates Cdc25A and Cdc25C. Phosphorylated Cdc25A is ubiquitylated and degraded, leaving Cdk2/cyclin complexes in their inactive form, resulting in S-phase and G2-phase arrest. Phosphorylated Cdc25C binds to 14-3-3 proteins and is exported from the nucleus, leaving Cdk1/cyclin B complexes in the inactive form, resulting in G2 arrest.
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