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Expert Opin Drug Discov. 2013 Jun;8(6):621-40. doi: 10.1517/17460441.2013.788496. Epub 2013 Apr 18.

Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies.

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Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, London SM2 5NG, UK.



Checkpoint kinase (CHK) inhibitors offer the promise of enhancing the effectiveness of widely prescribed cancer chemotherapies and radiotherapy by inhibiting the DNA damage response, as well as the potential for single agent efficacy.


This article surveys structural insights into the checkpoint kinases CHK1 and CHK2 that have been exploited to enhance the selectivity and potency of small molecule inhibitors. Furthermore, the authors review the use of mechanistic cellular assays to guide the optimisation of inhibitors. Finally, the authors discuss the status of the current clinical candidates and emerging new clinical contexts for CHK1 and CHK2 inhibitors, including the prospects for single agent efficacy.


Protein-bound water molecules play key roles in structural features that can be targeted to gain high selectivity for either enzyme. The results of early phase clinical trials of checkpoint inhibitors have been mixed, but significant progress has been made in testing the combination of CHK1 inhibitors with genotoxic chemotherapy. Second-generation CHK1 inhibitors are likely to benefit from increased selectivity and oral bioavailability. While the optimum therapeutic context for CHK2 inhibition remains unclear, the emergence of single agent preclinical efficacy for CHK1 inhibitors in specific tumour types exhibiting constitutive replication stress represents exciting progress in exploring the therapeutic potential of these agents.

[Indexed for MEDLINE]
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