A Small-Molecule Inhibitor of TopBP1 Exerts Anti-myc Activity and Synergy With PARP Inhibitors

Authors

Fang-Tsyr Lin
Kang Liu
Lidija A Wilhelms Garan
Helena Folly-Kossi
Yongcheng Song
Shwu-Jiuan Lin
Weei-Chin Lin

Publication Date

10-31-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2307793120

PMID

37878724

PMCID

PMC10622895

PubMedCentral® Posted Date

10-25-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Humans, DNA-Binding Proteins, Poly(ADP-ribose) Polymerase Inhibitors, Tumor Suppressor Protein p53, Nuclear Proteins, Molecular Docking Simulation, Carrier Proteins, TopBP1, BRCT domains, small-molecule inhibitors, MYC, p53

Abstract

We have previously identified TopBP1 (topoisomerase IIβ-binding protein 1) as a promising target for cancer therapy, given its role in the convergence of Rb, PI(3)K/Akt, and p53 pathways. Based on this, we conducted a large-scale molecular docking screening to identify a small-molecule inhibitor that specifically targets the BRCT7/8 domains of TopBP1, which we have named 5D4. Our studies show that 5D4 inhibits TopBP1 interactions with E2F1, mutant p53, and Cancerous Inhibitor of Protein Phosphatase 2A. This leads to the activation of E2F1-mediated apoptosis and the inhibition of mutant p53 gain of function. In addition, 5D4 disrupts the interaction of TopBP1 with MIZ1, which in turn allows MIZ1 to bind to its target gene promoters and repress MYC activity. Moreover, 5D4 inhibits the association of the TopBP1-PLK1 complex and prevents the formation of Rad51 foci. When combined with inhibitors of PARP1/2 or PARP14, 5D4 synergizes to effectively block cancer cell proliferation. Our animal studies have demonstrated the antitumor activity of 5D4 in breast and ovarian cancer xenograft models. Moreover, the effectiveness of 5D4 is further enhanced when combined with a PARP1/2 inhibitor talazoparib. Taken together, our findings strongly support the potential use of TopBP1-BRCT7/8 inhibitors as a targeted cancer therapy.

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