title: Single-agent inhibition of Chk1 is antiproliferative in human cancer cell lines in vitro and inhibits tumor xenograft growth in vivo.
abstract: Chk1 is a serine/threonine kinase that plays several important roles in the cellular response to genotoxic stress. Since many current standard-of-care therapies for human cancer directly damage DNA or inhibit DNA synthesis, there is interest in using small molecule inhibitors of Chk1 to potentiate their clinical activity. Additionally, Chk1 is known to be critically involved in cell cycle progression of unperturbed cells. Therefore, it is plausible that treatment with a Chkl inhibitor alone could also be an efficacious cancer therapy. Here we report that Chk1-A, a potent and highly selective small molecule inhibitor of Chk1, is antiproliferative as a single agent in a variety of human cancer cell lines in vitro. The inhibition of proliferation is associated with collapse of DNA replication and apoptosis. Rapid decreases in inhibitory phosphorylation of CDKs and a concomitant increase in CDK kinase activity and chromatin loading of Cdc45 suggest that the antiproliferative and proapoptotic activity of Chk1-A is at least in part due to deregulation of DNA synthesis. We extend these in vitro studies by demonstrating that Chk1-A inhibits the growth of tumor xenografts in vivo in a treatment regimen that is well tolerated. Together, these results suggest that single-agent inhibition of Chk1 may be an effective treatment strategy for selected human malignancies.
authors.affiliation: Cell Biology, Array BioPharma, Inc., Boulder, CO 80301, USA. kurtisdavies@hotmail.com
authors.forename: Kurtis D
authors.initials: KD
authors.lastname: Davies
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Humphries
authors.forename: Francis X
authors.initials: FX
authors.lastname: Sullivan
authors.forename: Ira
authors.initials: I
authors.lastname: von Carlowitz
authors.forename: Yvan
authors.initials: Y
authors.lastname: Le Huerou
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohr
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lyon
authors.forename: Indrani
authors.initials: I
authors.lastname: Gunawardana
authors.forename: Mark
authors.initials: M
authors.lastname: Chicarelli
authors.forename: Eli
authors.initials: E
authors.lastname: Wallace
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D005260:Female; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse