2. Academic Validation
  3. SGSS05-NS3, a covalent SETD8 inhibitor that activates p53 pathway in neuroblastoma

SGSS05-NS3, a covalent SETD8 inhibitor that activates p53 pathway in neuroblastoma

  • J Exp Clin Cancer Res. 2025 Dec 19;45(1):5. doi: 10.1186/s13046-025-03565-7.
Zhihui Liu 1,  Sukriti Bagchi 1,  Chunhua Yan 2,  Ying Hu 2,  Gil Blum 3 4,  Anqi Ma 5,  Jian Jin 5,  Minkui Luo 3 4 6,  Sebastiano Di Bella 7,  Francesco Verona 8,  Ettore Appella 9,  Giuseppe Giannini 10 11,  Carol J Thiele 12,  Veronica Veschi 13 14
Affiliations

Affiliations

  • 1 Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, CRC, 1-3940, 10 Center Drive MSC-1105, Bethesda, MD, 20892, USA.
  • 2 Center for Biomedical Informatics and Information Technology, Center for Cancer Research, National Cancer Institute, Rockville, MD, USA.
  • 3 Tri-Institutional PhD Program of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 4 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 5 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, Oncological Sciences and Neuroscience, Tisch Cancer Institute, New York, NY, 10029, USA.
  • 6 Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, 10021, USA.
  • 7 Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy.
  • 8 Department of Health Promotion Sciences, Internal Medicine and Medical Specialties, University of Palermo, Palermo, 90127, Italy.
  • 9 Chemical Immunology Section, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD, USA.
  • 10 Department of Molecular Medicine, University of Rome La Sapienza, Rome, 00161, Italy.
  • 11 Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, 00161, Italy.
  • 12 Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, CRC, 1-3940, 10 Center Drive MSC-1105, Bethesda, MD, 20892, USA. [email protected].
  • 13 Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, CRC, 1-3940, 10 Center Drive MSC-1105, Bethesda, MD, 20892, USA. [email protected].
  • 14 Department of Molecular Medicine, University of Rome La Sapienza, Rome, 00161, Italy. [email protected].
PMID: 41419951 DOI: 10.1186/s13046-025-03565-7
Abstract

BACKGROUND: High-risk neuroblastoma (NB) is one of the most aggressive pediatric tumors accounting for 15% of all pediatric oncology deaths, and with less than 50% of patients experience long-term survival despite intense multimodal treatment. The tumor suppressor p53 is rarely (2%) mutated in NB but its functions are diminished in the majority of these tumors. Multiple mechanisms have been identified that attenuate the activity of p53 in MYCN-amplified (MYCN-amp) NB cells, but fewer mechanisms of p53 inactivation have been revealed in MYCN-WT NBs. Thus, a major challenge is to identify novel targeted therapies for high-risk NB (HR-NB) patients, specifically for the large fraction (70%) that present with MYCN-WT. Previously, we identified SETD8, the H4K20me1 methyltransferase, as a crucial epigenetic regulator of growth and differentiation in NB. In addition to targeting Other non-histone proteins, SETD8 monomethylates p53 on lysine 382 (p53K382me1), attenuating its pro-apoptotic and growth arrest functions. Genetic and pharmacological (UNC0379) inhibition of SETD8 impairs NB growth in vivo. METHODS: IC50 and IVTI (in vitro therapeutic index) of SGSS05-NS3, a SETD8 inhibitor, were measured in a broad collection of MYCN-WT and MYCN-amp NB cell lines. We took advantage of RNA-seq transcriptome analysis, in vitro functional assays and in vivo preclinical NB models. RESULTS: To identify targeted therapies that are less toxic for HR-NB, we evaluated a more specific SETD8 inhibitor with enhanced activity and selectivity, SGSS05-NS3. Our results indicated that in NB cells in vitro treatment with SGSS05-NS3 rescues the canonical p53 functions leading to increases in p53 protein levels and of its target p21 by decreasing p53K382me1, impairing NB cell viability and inducing caspase-dependent cell death. Gene expression profile (RNA-seq analysis) confirmed that the most significantly upregulated genes upon SGSS05-NS3 treatment were among the p53 pathway targets. Pharmacological and genetic SETD8 inhibition restores p53-mediated DNA damage response. In pre-clinical xenograft NB models, pharmacological SETD8 inhibition by SGSS05-NS3 conferred a significant survival advantage in MYCN-WT NB. CONCLUSIONS: Our study provides further evidence for targeting SETD8 as a therapeutic strategy in NB, alone or in combination with Topotecan.

Keywords

Bliss value; MYCN; Neuroblastoma; P53 methylation; Synergy score; Topotecan; UNC0379.

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