Significance
Amplification of MYC and mutation of p53 are frequently found in human cancers, yet directly targeting it has proven difficult. Thus, exploring alternative methods to hinder their activities would significantly impact cancer treatment. TopBP1 (topoisomerase IIβ-binding protein 1) functions at the convergent point of Rb, PI3K/Akt, and p53 pathways, making it a promising cancer therapeutic target. Our high-throughput screening led to the development of a previously undescribed small-molecular inhibitor targeting the BRCT7/8 domains of TopBP1. In addition to inhibiting mutant p53 function, this inhibitor can block MYC activity by freeing MIZ1, a MYC inhibitor, from TopBP1. It can also inhibit Rad51 foci formation and synergize with inhibitors of PARP1/2 or PARP14, providing a potential synthetic lethal targeted cancer therapy.
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.
