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We previously developed CCC<\/jats:styled-content>\u2010002, a MYCN<\/jats:italic><\/jats:styled-content>\u2010selective pyrrole\u2010imidazole polyamide conjugated to a DNA<\/jats:styled-content> alkylating agent. Administration of CCC<\/jats:styled-content>\u2010002 to MYCN<\/jats:italic><\/jats:styled-content>\u2010amplified (MYCN<\/jats:italic><\/jats:styled-content>\u2010amp) neuroblastoma cells triggered the activation of DNA<\/jats:styled-content> damage responses. Here, we demonstrated that among the DNA<\/jats:styled-content> damage response inhibitors, ataxia telangiectasia and Rad3\u2010related (ATR<\/jats:styled-content>) inhibitors synergized with CCC<\/jats:styled-content>\u2010002 to suppress DNA<\/jats:styled-content> repair\u2010related genes and induce apoptosis in MYCN<\/jats:italic><\/jats:styled-content>\u2010amp neuroblastoma cells. A synergistic antitumor effect was verified in an SK<\/jats:styled-content>\u2010N\u2010BE<\/jats:styled-content>(2) xenograft mouse model, in which the combined use of CCC<\/jats:styled-content>\u2010002 and ATR<\/jats:styled-content> inhibitor at low doses significantly inhibited tumor progression. Notably, SK<\/jats:styled-content>\u2010N\u2010BE<\/jats:styled-content>(2) and SK<\/jats:styled-content>\u2010N\u2010DZ<\/jats:styled-content> cells, which showed ATM<\/jats:styled-content> activation after CCC<\/jats:styled-content>\u2010002 treatment, exhibited high sensitivity to the combined treatment of ATR<\/jats:styled-content> inhibitors. Comprehensive analysis of the gene expression profiles revealed that the combination treatment upregulated apoptosis\u2010related pathways and downregulated DNA<\/jats:styled-content> repair\u2010related pathways. After the combined treatment of CCC<\/jats:styled-content>\u2010002 and ATR<\/jats:styled-content> inhibitor, MYCN<\/jats:italic><\/jats:styled-content>\u2010amp cells showed less FISH<\/jats:styled-content> probe signal and mRNA<\/jats:styled-content> expression of MYCN<\/jats:italic><\/jats:styled-content>, which was accompanied by an increase in DNA<\/jats:styled-content> damage markers in the genomic region of MYCN<\/jats:italic><\/jats:styled-content>, highlighting that ATR<\/jats:styled-content> inhibitors synergize with CCC<\/jats:styled-content>\u2010002 and play a crucial role in the development of a novel MYCN<\/jats:styled-content>\u2010targeting therapy for MYCN<\/jats:italic><\/jats:styled-content>\u2010amp neuroblastoma.<\/jats:p>","DOI":"10.1111\/cas.70043","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T16:45:32Z","timestamp":1741711532000},"page":"1691-1702","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["ATR<\/scp> Inhibition Synergizes With Alkylating PI<\/scp> Polyamide Targeting MYCN<\/i><\/scp> by Suppressing DNA<\/scp> Repair in MYCN<\/i><\/scp>\u2010Amplified Neuroblastoma"],"prefix":"10.1111","volume":"116","author":[{"given":"Xiaoyi","family":"Lai","sequence":"first","affiliation":[{"name":"Division of Innovative Cancer Therapeutics Chiba Cancer Center Research Institute Chiba Japan"},{"name":"Graduate School of Medical and Pharmaceutical Sciences, Chiba University Chiba 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