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Novel BRD4-p53 Inhibitor SDU-071 Suppresses Proliferation and Migration of MDA-MB-231 Triple-Negative Breast Cancer
Shumei Wang1, Kang Lei1,2, Hsien-Tsung Lai3
1Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Abstract:
A promising alternative for cancer treatment involves targeted inhibition of the epigenetic regulator bromodomain-containing protein 4 (BRD4); however, available BRD4 inhibitors are constrained by their potency, oral bioavailability, and cytotoxicity. Herein, to overcome the drawback of the translational BRD4 inhibitors, we describe a novel BRD4-p53 inhibitor, SDU-071, which suppresses BRD4 interaction with the p53 tumor suppressor and its biological activity in MDA-MB-231 triple-negative breast cancer (TNBC) cells in vitro and in vivo. This novel small-molecule BRD4-p53 inhibitor suppresses cell proliferation, migration, and invasion by downregulating the expression of BRD4-targeted genes, such as c-Myc and Mucin 5AC, and inducing cell cycle arrest and apoptosis, as demonstrated in cultured MDA-MB-231 TNBC cells. Its antitumor activity is illustrated in an orthotopic mouse xenograft mammary tumor model. Overall, our results show that SDU-071 is a viable option for potentially treating TNBC as a new BRD4-p53 inhibitor.
Insights
A novel small-molecule inhibitor, SDU-071, effectively targets the bromodomain-containing protein 4 (BRD4)-p53 interaction. This compound shows promise for treating triple-negative breast cancer (TNBC) by suppressing tumor growth and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Targeted inhibition of bromodomain-containing protein 4 (BRD4) is a potential cancer therapy.
- Existing BRD4 inhibitors face challenges with potency, bioavailability, and cytotoxicity.
Purpose of the Study:
- To develop a novel BRD4 inhibitor that overcomes limitations of current therapies.
- To investigate the efficacy of SDU-071, a new BRD4-p53 inhibitor, in triple-negative breast cancer (TNBC).
Main Methods:
- SDU-071's ability to suppress BRD4-p53 interaction was assessed in MDA-MB-231 TNBC cells.
- In vitro studies evaluated SDU-071's impact on cell proliferation, migration, invasion, cell cycle, and apoptosis.
- In vivo efficacy was tested using an orthotopic mouse xenograft mammary tumor model.
Main Results:
- SDU-071 suppressed proliferation, migration, and invasion in MDA-MB-231 cells.
- Downregulation of BRD4-targeted genes (e.g., c-Myc, Mucin 5AC), cell cycle arrest, and apoptosis were observed.
- SDU-071 demonstrated significant antitumor activity in a TNBC mouse model.
Conclusions:
- SDU-071 is a novel small-molecule inhibitor targeting the BRD4-p53 interaction.
- SDU-071 exhibits potent anti-TNBC activity in vitro and in vivo.
- SDU-071 represents a promising therapeutic candidate for TNBC treatment.
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