biostudies-literatureWalton MICancer Research UKMedical Research CouncilNational Institute for Health Research (NIHR)Wellcome Trust5650-61https://www.ebi.ac.uk/biostudies/studies/S-EPMC3474704biostudies-literatureUnknown18(20)<h4>Purpose</h4>Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity.<h4>Experimental design</h4>Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenograftClinical cancer research : an official journal of the American Association for Cancer ResearchCCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs.PMC3474704A10334A11566A8274091763Z/10/ZC309/A11566C309/A827411566C1060/A10334Raynaud FIBox GMatthews TPChesler LGarrett MDEccles SAEve PDSmith ELLainchbury MHayes AValenti MRJamin YReader JCAherne GWDe Haven Brandon AKBoxall KJRobinson SPCollins IHallsworth AWalton MIfalseCCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs.<h4>Purpose</h4>Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity.<h4>Experimental design</h4>Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenograft2012-01-01T00:00:00Z2012 Oct2026-05-01T23:16:20.782Z2019-03-27T00:59:11ZS-EPMC34747042292980610.1158/1078-0432.CCR-12-132210.1158/1078-0432.ccr-12-1322