ArticleClinical cancer research : an official journal of the American Association for Cancer Research2012
CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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56 citing papers in PubMed, 92 citations in OpenAlex.
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- CHK1 inhibition increases the therapeutic response to radiotherapy via antitumor immunity in ARID1A-deficient colorectal cancer.Cell death & disease · 2025Article
- FOXM1 Promotes Non-Small Cell Lung Cancer Progression by Increasing CHEK1 Expression.Current medical science · 2025Article
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- Novel Cellular Functions of ATR for Therapeutic Targeting: Embryogenesis to Tumorigenesis.International journal of molecular sciences · 2023Review
- The Adaptive Mechanisms and Checkpoint Responses to a Stressed DNA Replication Fork.International journal of molecular sciences · 2023Review
- Investigations of the novel checkpoint kinase 1 inhibitor SRA737 in non-small cell lung cancer and colorectal cancer cells of differingExploration of targeted anti-tumor therapy · 2023Article
- Toward more potent imidazopyridine inhibitors of Candida albicans Bdf1: Modeling the role of structural waters in selective ligand binding.Journal of computational chemistry · 2022Article
- Mutation of the RelA(p65) Thr505 phosphosite disrupts the DNA replication stress response leading to CHK1 inhibitor resistance.The Biochemical journal · 2022Article
- Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway.The Biochemical journal · 2022Article
- DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities.Experimental & molecular medicine · 2022Review
- The identification of hub biomarkers and pathways in lung cancer and prognostic evaluation.Translational cancer research · 2022Article
- Genome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells.Cancer research · 2022Article
- Identification of hub genes and their correlation with infiltration of immune cells inFrontiers in immunology · 2022Article
- Integrative Bioinformatics Analysis Reveals CHEK1 and UBE2C as Luminal A Breast Cancer Subtype Biomarkers.Frontiers in genetics · 2022Article
- Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer.Genome medicine · 2021Article
- Checkpoint Kinase 1 (Chk1) inhibition fails to activate the Stimulator of Interferon Genes (STING) innate immune signalling in a human coculture cancer system.Molecular biomedicine · 2021Article
- Control Analysis of Protein-Protein Interaction Network Reveals Potential Regulatory Targets for MYCN.Frontiers in oncology · 2021Article
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Authors and funding
20 authors at 1 institution in 1 country.
Funding
Abstract
purposeMany 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. EXPERIMENTAL
designCellular 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 xenografts by growth delay.
resultsCCT244747 inhibited cellular CHK1 activity (IC(50) 29-170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G(2) arrest in multiple tumor cell lines. Biomarkers of CHK1 (pS296 CHK1) activity and cell-cycle inactivity (pY15 CDK1) were induced by genotoxics and inhibited by CCT244747 both in vitro and in vivo, producing enhanced DNA damage and apoptosis. Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activity of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in several human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition. CCT244747 also showed marked antitumor activity as a single agent in a MYCN-driven neuroblastoma.
conclusionCCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.