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Published on: October 3, 2025
Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy
Pinki Chowdhury1, Gregory E Lin2, Kang Liu1
1Section of Hematology/Oncology, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
The progression of many solid tumours is driven by deregulation of multiple common pathways, particularly Rb, PI(3)K/Akt and p53. Prior studies identified TopBP1 as a key mediator for the oncogenic gain-of-function activities of mutant p53 (mutp53) in cancer. In Akt-hyperactive cancer, TopBP1 forms oligomers and represses E2F1-dependent apoptosis. Here we perform a molecular docking screening and identify a lead compound, calcein, capable of blocking TopBP1 oligomerization and p53 binding, resulting in re-activation of E2F1-dependent apoptosis and blockade of mutp53 gain-of-function. Calcein AM, the cell-permeable derivative of calcein, shows significant antitumour activity in a wide spectrum of cultured cancer cells harbouring high TopBP1 levels. These biochemical findings are recapitulated in breast cancer xenograft models. Thus, our study provides proof-of-concept evidence for targeting TopBP1, a convergent point of multiple pathways, as a cancer therapy.
Insights
Researchers discovered calcein, a compound that blocks TopBP1, a protein driving cancer growth. This drug reactivates apoptosis and shows anti-cancer effects in models, offering a new therapeutic strategy for solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Solid tumor progression involves deregulation of pathways like Rb, PI(3)K/Akt, and p53.
- TopBP1 is identified as a mediator of mutant p53 (mutp53) oncogenic gain-of-function.
- In Akt-hyperactive cancers, TopBP1 oligomerization represses E2F1-dependent apoptosis.
Purpose of the Study:
- To identify compounds that inhibit TopBP1 oligomerization and mutp53 gain-of-function.
- To evaluate the anti-cancer potential of identified compounds.
Main Methods:
- Molecular docking screening to identify lead compounds.
- Biochemical assays to assess TopBP1 inhibition and apoptosis.
- In vitro studies using cancer cell lines.
- In vivo studies using breast cancer xenograft models.
Main Results:
- Calcein identified as a lead compound blocking TopBP1 oligomerization and p53 binding.
- Calcein reactivates E2F1-dependent apoptosis and blocks mutp53 gain-of-function.
- Calcein AM demonstrates significant anti-tumor activity in various cancer cells and xenograft models.
Conclusions:
- Targeting TopBP1, a convergence point of multiple cancer pathways, is a viable therapeutic strategy.
- Calcein and its derivatives represent a promising new class of anti-cancer agents.
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