Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
Natalie Timme1, Youjia Han1, Shuai Liu2
1Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center (ECRC) of the Charité and the Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany.
Abstract:
Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.
Insights
Dual kinase-bromodomain inhibitors targeting BRD4 and PLK1 show potent antitumor activity in pediatric cancers. These novel small molecules effectively reduced tumor growth and induced cell death in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Simultaneous inhibition of multiple targets can enhance therapeutic response duration.
- BRD4 and PLK1 are key regulators in cancer pathways.
Purpose of the Study:
- To screen dual kinase-bromodomain inhibitors for antitumor activity in pediatric cancer cell lines.
- To evaluate the efficacy of dual BRD4 and PLK1 inhibition in preclinical pediatric cancer models.
Main Methods:
- Screening of 49 dual BRD4/PLK1 inhibitors in pediatric tumor cell lines.
- Assessment of antitumor activity, proliferation, apoptosis, and gene expression (RNA sequencing).
- In vivo studies using patient-derived xenografts treated with UMB103.
Main Results:
- Identified two dual inhibitors with potent, tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma.
- Low nanomolar concentrations of dual inhibitors suppressed proliferation and induced apoptosis.
- Reduced MYCN-driven gene expression and significant tumor regression in xenografts were observed.
Conclusions:
- Concurrent inhibition of BRD4 and PLK1 with single small molecules demonstrates strong, specific antitumor effects in preclinical pediatric cancer models.
- Dual kinase-bromodomain inhibitors represent a promising therapeutic strategy for pediatric cancers.
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