Abstract:
:Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2-M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a therapeutic strategy, inhibition of ChK1 should potentiate the antitumor effect of chemotherapeutic agents by inactivating the postreplication checkpoint, causing premature entry into mitosis with damaged DNA resulting in mitotic catastrophe. Here, we describe the characterization of GNE-900, an ATP-competitive, selective, and orally bioavailable ChK1 inhibitor. In combination with chemotherapeutic agents, GNE-900 sustains ATR/ATM signaling, enhances DNA damage, and induces apoptotic cell death. The kinetics of checkpoint abrogation seems to be more rapid in p53-mutant cells, resulting in premature mitotic entry and/or accelerated cell death. Importantly, we show that GNE-900 has little single-agent activity in the absence of chemotherapy and does not grossly potentiate the cytotoxicity of gemcitabine in normal bone marrow cells. In vivo scheduling studies show that optimal administration of the ChK1 inhibitor requires a defined lag between gemcitabine and GNE-900 administration. On the refined combination treatment schedule, gemcitabine's antitumor activity against chemotolerant xenografts is significantly enhanced and dose-dependent exacerbation of DNA damage correlates with extent of tumor growth inhibition. In summary, we show that in vivo potentiation of gemcitabine activity is mechanism based, with optimal efficacy observed when S-phase arrest and release is followed by checkpoint abrogation with a ChK1 inhibitor.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Blackwood E,Epler J,Yen I,Flagella M,O'Brien T,Evangelista M,Schmidt S,Xiao Y,Choi J,Kowanetz K,Ramiscal J,Wong K,Jakubiak D,Yee S,Cain G,Gazzard L,Williams K,Halladay J,Jackson PK,Malek Sdoi
10.1158/1535-7163.MCT-12-1218subject
Has Abstractpub_date
2013-10-01 00:00:00pages
1968-80issue
10eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-12-1218journal_volume
12pub_type
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