Language
English
Publication Date
8-7-2026
Journal
Science Advances
DOI
10.1126/sciadv.aeg1996
PMID
42555732
PMCID
PMC13440399
PubMedCentral® Posted Date
8-5-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-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–driven 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 EGFR-mutated non–small 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.
Keywords
Humans, Pyrimidines, Drug Resistance, Neoplasm, Aniline Compounds, Indoles, Animals, DNA-Binding Proteins, Poly(ADP-ribose) Polymerase Inhibitors, Acrylamides, Cell Line, Tumor, Mice, Female, Xenograft Model Antitumor Assays, Carrier Proteins, Lung Neoplasms, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Nuclear Proteins
Published Open-Access
yes
Recommended Citation
Lin, Fang-Tsyr; Lin, Shwu-Jiuan; Liu, Kang; et al., "Development of a Structurally Distinct TopBP1 Inhibitor That Enhances Parp Blockade and Reverses Osimertinib Resistance" (2026). Faculty, Staff and Students Publications. 8131.
https://digitalcommons.library.tmc.edu/baylor_docs/8131