CHK2 kinase: cancer susceptibility and cancer therapy – two sides of the same coin?

Antoni, Laurent; Sodha, Nayanta; Collins, Ian; Garrett, Michelle D.

doi:10.1038/nrc2251

Cited by 267 publications

(272 citation statements)

References 136 publications

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“…6 DBQ is an ATP-competitive inhibitor with an IC 50 below 183 nM for Chk2 but it is not specific for Chk2. 10,25,29 Overall, the global structures of the protein molecules in the two cocrystal structures are almost identical. The binding mode of DBQ (see Fig.…”

Section: Binding Mode Of Nsc 109555mentioning

confidence: 90%

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

et al. 2008

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Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNAdamaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC 50 = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATPbinding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

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Section: Binding Mode Of Nsc 109555mentioning

confidence: 90%

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

et al. 2008

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“…ChkII may be required to manage genomic instability, and both ChkII and p53 are activated by at these phosphorylation sites by ATM in response to DNA double strand breaks [204]. Phosphorylated ChkII induces cell cycle arrest, promotes DNA repair and activates apoptosis [204].…”

Section: Checkpoint II Inhibitionmentioning

confidence: 99%

“…The clinical utility of ChkII inhibitors is uncertain. It has been postulated that, in combination with anti-cancer therapies that induce double strand DNA breaks, including radiotherapy and chemotherapy agents such as topoisomerase inhibitors, ChkII inhibitors may be of benefit to patients with concurrent DNA repair pathway abnormalities [204]. However, the main effect of ChkII activation may be to induce apoptosis in response to DNA damage.…”

Section: Checkpoint II Inhibitionmentioning

confidence: 99%

Vascular-targeted agents for the treatment of angiosarcoma

Young

Woll

Staton

et al. 2013

Cancer Chemother Pharmacol

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“…One of the effector kinases is CHK2, a mammalian homolog of the budding yeast (Saccharomyces cerevisiae) Rad53 and the fission yeast (Schizosaccharomyces pombe) Cds1 (Allen et al, 1994;Murakami and Okayama, 1995;Antoni et al, 2007). In yeast, Rad53 is activated by both DNA damage and replication block, whereas Cds1 functions mainly in the replication checkpoint pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Upon sensing the damage signals, ATM and ATR phosphorylate CHK2 on Thr68, which then leads to activation of CHK2. Once activated, CHK2 phosphorylates its downstream targets such as p53, Cdc25 and FOXM1, leading to growth arrest, apoptosis, or DNA repair (Iliakis et al, 2003;Antoni et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1

Huang

Lin

et al. 2009

Oncogene

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Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68. However, it remains to be determined whether and how TTK/hMps1 responds to DNA damage. In this report, we present evidence that TTK/hMps1 can be induced by DNA damage in normal human fibroblasts. Interestingly, the induction depends on CHK2 because CHK2-targeting small interfering RNA or a CHK2 inhibitor abolishes the increase. Such induction is mediated through phosphorylation of TTK/hMps1 at Thr288 by CHK2 and requires the CHK2 SQ/TQ cluster domain/forkhead-associated domain. In cells, TTK/ hMps1 phosphorylation at Thr288 is induced by DNA damage and forms nuclear foci, which colocalize partially with c-H2AX. Reexpression of TTK/hMps1 T288A mutant in TTK/hMps1-knockdown cells causes a defect in G 2 /M arrest, suggesting that phosphorylation at this site participates in the proper checkpoint execution. Our study uncovered a regulatory loop between TTK/hMps1 and CHK2 whereby DNA damage-activated CHK2 may facilitate the stabilization of TTK/hMps1, therefore maintaining the checkpoint control.

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CHK2 kinase: cancer susceptibility and cancer therapy – two sides of the same coin?

Cited by 267 publications

References 136 publications

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

Vascular-targeted agents for the treatment of angiosarcoma

The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1

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