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Adv."],"published-print":{"date-parts":[[2026,8,7]]},"abstract":"<jats:p>\n                    Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase II\u03b2-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7\/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7\/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship\u2013driven optimization, we developed CS18 as a potent and selective BRCT7\/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, restores E2F1-mediated apoptosis, and induces mitotic catastrophe. It exhibits broad-spectrum anticancer activity and synergizes with poly(ADP-ribose) polymerase (PARP) inhibitors in multiple cancer types and enhances osimertinib sensitivity in\n                    <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                    -mutated non\u2013small cell lung cancer (NSCLC) cells. CS18 demonstrates efficacy in patient-derived breast cancer xenografts and overcomes osimertinib resistance in refractory NSCLC in vivo. These findings establish CS18 as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg1996","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T18:01:42Z","timestamp":1785952902000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Development of a structurally distinct TopBP1 inhibitor that enhances PARP blockade and reverses osimertinib resistance"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5160-0047","authenticated-orcid":true,"given":"Fang-Tsyr","family":"Lin","sequence":"first","affiliation":[{"name":"Section of Hematology\/Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Dan L. 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