ArticlePloS one2014
The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Exploring the multifaceted Dbf4-dependent kinase from temporal, spatial, and substrate repertoire perspectives.Communications biology · 2026Review
- USP48 promotes tumour progression through the deubiquitination and stabilization of DBF4 in clear cell renal carcinoma.Cancer cell international · 2026Article
- Identifying TP53RK as a key regulator of colorectal cancer survival and a potential therapeutic target.Scientific reports · 2025Article
- Multi-Pathway Study for Oxaliplatin Resistance Reduction.Current issues in molecular biology · 2025Review
- The prognostic significance and potential mechanism of DBF4 zinc finger in hepatocellular carcinoma.Scientific reports · 2024Article
- CDC7 as a novel biomarker and druggable target in cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2022Review
- Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway.Biomedicines · 2022Article
- Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication.Molecular cell · 2021Article
- Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.Nature communications · 2020Article
- Preparation for DNA replication: the key to a successful S phase.FEBS letters · 2019Review
- Differential Sensitivity to CDK2 Inhibition Discriminates the Molecular Mechanisms of CHK1 Inhibitors as Monotherapy or in Combination with the Topoisomerase I Inhibitor SN38.ACS pharmacology & translational science · 2019Article
- A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation.Frontiers in immunology · 2019Article
- Discovery and Structure-Activity-Relationship Study of N-Alkyl-5-hydroxypyrimidinone Carboxamides as Novel Antitubercular Agents Targeting Decaprenylphosphoryl-β-d-ribose 2'-Oxidase.Journal of medicinal chemistry · 2018Article
- DDK Has a Primary Role in Processing Stalled Replication Forks to Initiate Downstream Checkpoint Signaling.Neoplasia (New York, N.Y.) · 2018Article
- O Cdc7 kinase where art thou?Current genetics · 2018Article
- CDC7-dependent transcriptional regulation of RAD54L is essential for tumorigenicity and radio-resistance of glioblastoma.Translational oncology · 2018Article
- Role of MCM2-7 protein phosphorylation in human cancer cells.Cell & bioscience · 2018Review
- DDK Promotes Tumor Chemoresistance and Survival via Multiple Pathways.Neoplasia (New York, N.Y.) · 2017Article
- Reversal of DDK-Mediated MCM Phosphorylation by Rif1-PP1 Regulates Replication Initiation and Replisome Stability Independently of ATR/Chk1.Cell reports · 2017Article
- The structural basis of the dominant negative phenotype of the Gαi1β1γ2 G203A/A326S heterotrimer.Acta pharmacologica Sinica · 2016Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Cdc7-Dbf4 kinase or DDK (Dbf4-dependent kinase) is required to initiate DNA replication by phosphorylating and activating the replicative Mcm2-7 DNA helicase. DDK is overexpressed in many tumor cells and is an emerging chemotherapeutic target since DDK inhibition causes apoptosis of diverse cancer cell types but not of normal cells. PHA-767491 and XL413 are among a number of potent DDK inhibitors with low nanomolar IC50 values against the purified kinase. Although XL413 is highly selective for DDK, its activity has not been extensively characterized on cell lines. We measured anti-proliferative and apoptotic effects of XL413 on a panel of tumor cell lines compared to PHA-767491, whose activity is well characterized. Both compounds were effective biochemical DDK inhibitors but surprisingly, their activities in cell lines were highly divergent. Unlike PHA-767491, XL413 had significant anti-proliferative activity against only one of the ten cell lines tested. Since XL413 did not effectively inhibit DDK in multiple cell lines, this compound likely has limited bioavailability. To identify potential leads for additional DDK inhibitors, we also tested the cross-reactivity of ∼400 known kinase inhibitors against DDK using a DDK thermal stability shift assay (TSA). We identified 11 compounds that significantly stabilized DDK. Several inhibited DDK with comparable potency to PHA-767491, including Chk1 and PKR kinase inhibitors, but had divergent chemical scaffolds from known DDK inhibitors. Taken together, these data show that several well-known kinase inhibitors cross-react with DDK and also highlight the opportunity to design additional specific, biologically active DDK inhibitors for use as chemotherapeutic agents.
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Registered trials
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.