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Inhibition of p53 DNA binding by a small molecule protects mice from radiation toxicity.

Authors
  • Li, Qingliang1
  • Karim, Rezaul M2, 3
  • Cheng, Mo2
  • Das, Mousumi1
  • Chen, Lihong1
  • Zhang, Chen4
  • Lawrence, Harshani R2
  • Daughdrill, Gary W5
  • Schonbrunn, Ernst2
  • Ji, Haitao2
  • Chen, Jiandong6
  • 1 Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.
  • 2 Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA.
  • 3 Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
  • 4 High-throughput Screening Facility, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 5 Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA.
  • 6 Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA. [email protected]
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Jul 01, 2020
Volume
39
Issue
29
Pages
5187–5200
Identifiers
DOI: 10.1038/s41388-020-1344-y
PMID: 32555331
Source
Medline
Language
English
License
Unknown

Abstract

Transcription factors are attractive therapeutic targets that are considered non-druggable because they do not have binding sites for small drug-like ligands. We established a cell-free high-throughput screening assay to search for small molecule inhibitors of DNA binding by transcription factors. A screen was performed using p53 as a target, resulting in the identification of NSC194598 that inhibits p53 sequence-specific DNA binding in vitro (IC50 = 180 nM) and in vivo. NSC194598 selectively inhibited DNA binding by p53 and homologs p63/p73, but did not affect E2F1, TCF1, and c-Myc. Treatment of cells with NSC194598 alone paradoxically led to p53 accumulation and modest increase of transcriptional output owing to disruption of the MDM2-negative feedback loop. When p53 was stabilized and activated by irradiation or chemotherapy drug treatment, NSC194598 inhibited p53 DNA binding and induction of target genes. A single dose of NSC194598 increased the survival of mice after irradiation. The results suggest DNA binding by p53 can be targeted using small molecules to reduce acute toxicity to normal tissues by radiation and chemotherapy.

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