The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Neuroblastoma (NB) is a common pediatric cancer with poor outcomes in high-risk cases.
• MYCN oncogene amplification occurs in ~20% of NB, driving aggressive disease.
• Proteolysis targeting chimaera (PROTAC) technology offers novel therapeutic strategies via targeted protein degradation.

Purpose of the Study:

• To investigate the therapeutic potential of dBET57, a novel BRD4-targeting PROTAC, in neuroblastoma.
• To elucidate the mechanism of action of dBET57 in NB cells and *in vivo* models.

Main Methods:

• Utilized dBET57, a PROTAC molecule targeting BRD4, in NB cell lines and xenograft models.
• Assessed cell proliferation, apoptosis, cell cycle, and migration.
• Performed RNA-seq and ChIP-seq analyses to identify downstream targets.
• Investigated the role of identified targets TBX3 and ZMYND8 in NB pathogenesis.

Main Results:

• dBET57 induced BRD4 ubiquitination, inhibited NB cell proliferation, and promoted apoptosis.
• dBET57 treatment led to cell cycle arrest and reduced cell migration.
• dBET57 demonstrated significant anti-proliferative effects in *in vivo* xenograft models.
• Mechanism involves targeting BET and MYCN protein families, disrupting the superenhancer (SE) landscape.
• Identified and validated TBX3 and ZMYND8 as key downstream targets of dBET57 in NB.

Conclusions:

• dBET57 exhibits potent anti-neuroblastoma activity both *in vitro* and *in vivo*.
• dBET57's mechanism involves BRD4/MYCN degradation and SE disruption, impacting key oncogenic drivers.
• dBET57 represents a promising novel therapeutic candidate for high-risk neuroblastoma treatment.