G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer - PubMed (original) (raw)

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G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer

N Bucher et al. Br J Cancer. 2008.

Abstract

Rigorous quality control steps, termed checkpoints, tightly regulate progression through the cell cycle. DNA-damaging chemotherapy and radiation activate functional cellular checkpoints. These checkpoints can facilitate DNA repair and promote cell death in unrepaired cells. There are at least three DNA damage checkpoints - at G1/S, S, and G2/M - as well as a mitotic spindle checkpoint. Most cancer cells harbour mutations in tumour suppressors and/or oncogenes, which impair certain cell checkpoints. Inhibiting the remaining cell checkpoints - particularly after exposure of cancer cells to chemotherapy and/or radiation - allows cell death, a strategy now being employed in cancer therapeutics. With our increasing knowledge of cell cycle regulation, many compounds have been developed to inhibit specific checkpoint components, particularly at the G2/M transition. One such target is checkpoint kinase-1 (Chk1). We review here the molecular framework of the cell cycle, the rationale for targeting Chk1, the preclinical concepts related to the development of Chk1 inhibitors, and the efficacy and safety results from Chk1 inhibitors now in phase I/II trials.

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Figure 1

Figure 1

Cell cycle checkpoint pathways. Once DNA damage is identified with the aid of sensors, the checkpoint transducers ATM and ATR undergo conformational change and/or localisation, resulting in their activation. Together with their mediators, ATM and ATR activate a series of downstream molecules, including the checkpoint transducer kinases. Checkpoint kinase-2 and Chk1 inactivate CDC25 phosphatases, culminating in cell cycle arrest.

References

    1. Anderes K, Blasina A, Chen E, Kornmann J, Kraynov E, Stempniak M, Register J, Ninkovic S, Fleur CL, O'Connor P (2006) Characterization of a novel and selective inhibitor of checkpoint kinase 1: breaching the tumor's last checkpoint defense against chemotherapeutic agents. Eur J Cancer Suppl 4: 115
    1. Arlander SJ, Eapen AK, Vroman BT, McDonald RJ, Toft DO, Karnitz LM (2003) Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress. J Biol Chem 278: 52572–52577 - PubMed
    1. Ashwell S (2007) AZD7762, a novel potent and selective inhibitor of checkpoint kinases. Drug development track special session 2: New Drugs on the Horizon 2. AACR Annual Meeting 2007; 15 April 2007; AstraZeneca Research and Development: Waltham, MA
    1. Bartek J, Falck J, Lukas J (2001) CHK2 kinase – a busy messenger. Nat Rev Mol Cell Biol 2: 877–886 - PubMed
    1. Bartek J, Lukas C, Lukas J (2004) Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 5: 792–804 - PubMed

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