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Development of a structurally distinct TopBP1 inhibitor that enhances PARP blockade and reverses osimertinib

Fang-Tsyr Lin1,2, Shwu-Jiuan Lin3,4, Kang Liu1,2

  • 1Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Science Advances
|August 5, 2026
PubMed

Insights

A new drug, CS18, targets Topoisomerase IIβ-binding protein 1 (TopBP1) to overcome cancer treatment resistance. This potent inhibitor shows broad anticancer activity and synergizes with other therapies, offering potential for precision oncology.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Therapeutic resistance is a major hurdle in cancer treatment, often driven by compensatory signaling pathways.
  • Topoisomerase IIβ-binding protein 1 (TopBP1) is a key scaffold protein overexpressed in aggressive cancers, integrating stress responses with oncogenic networks.
  • The BRCT7/8 domains of TopBP1 are critical for interactions with proteins like E2F1 and CIP2A, making them a promising therapeutic target.

Purpose of the Study:

  • To develop a potent and selective inhibitor targeting the BRCT7/8 domains of TopBP1.
  • To evaluate the anticancer activity and therapeutic potential of the novel inhibitor CS18.
  • To investigate the synergistic effects of CS18 with existing cancer therapies and its ability to overcome resistance.

Main Methods:

  • Docking-guided screening and structure-activity relationship optimization were employed to design and develop CS18.
  • In vitro assays were used to assess CS18's ability to disrupt TopBP1 complexes, suppress MYC, restore apoptosis, and induce mitotic catastrophe.
  • In vivo studies utilized patient-derived xenografts and refractory non-small cell lung cancer models to evaluate efficacy and synergy with PARP inhibitors and osimertinib.

Main Results:

  • CS18 was identified as a potent and selective inhibitor of TopBP1-BRCT7/8, disrupting oncogenic complexes without affecting DNA replication.
  • CS18 demonstrated broad-spectrum anticancer activity by suppressing MYC, restoring E2F1-mediated apoptosis, and inducing mitotic catastrophe.
  • CS18 showed significant synergy with PARP inhibitors across multiple cancer types, enhanced sensitivity to osimertinib in EGFR-mutated NSCLC, and proved effective in preclinical models of breast cancer and osimertinib-resistant NSCLC.

Conclusions:

  • CS18 is a chemically distinct TopBP1 inhibitor with significant therapeutic potential.
  • CS18 effectively overcomes therapeutic resistance mechanisms in various cancer models.
  • CS18 represents a promising candidate for advancing precision oncology strategies.

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