Identification by High-throughput In Silico Screening of Radio-protecting Compounds Targeting the DNA-binding Domain of the Tumor Suppressor p53

Cancer Genomics - Proteomics

KERSTIN HIRSCHFELDER²  THOMAS EFFERTH⁴  TOLGA EICHHORN⁴  R. LUISE KRAUTH-SIEGEL³  ROLF MERTENS⁶  CORINNA HILLER⁵  MARTIN FRANK¹  ROLF MÜLLER² 

[1] German Cancer Research Center, Molecular Structure Analysis (W160), Heidelberg, GermanyGerman Cancer Research Center, Molecular Structure Analysis (W160), Heidelberg, GermanyGerman Cancer Research Center, Molecular Structure Analysis (W160), Heidelberg, Germany;Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Saarbrücken, GermanyDepartment of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, GermanyDepartment of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Saarbrücken, GermanyDepartment of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Saarbrücken, GermanyDepartment of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, GermanyDepartment of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, GermanyDepartment of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Saarbrücken, GermanyDepartment of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany;Biochemistry Center, University of Heidelberg, Heidelberg, GermanyBiochemistry Center, University of Heidelberg, Heidelberg, GermanyBiochemistry Center, University of Heidelberg, Heidelberg, Germany;Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, GermanyDepartment of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, GermanyDepartment of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany;Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, GermanyInstitute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, GermanyInstitute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany;Department for Pediatrics, University Hospital Aachen, Aachen, GermanyDepartment for Pediatrics, University Hospital Aachen, Aachen, GermanyDepartment for Pediatrics, University Hospital Aachen, Aachen, Germany

关键词: p53;    molecular docking;    pharmacogenomics;    radioprotection;    tumor suppressor;    virtual drug screening;    in silico screening;   

DOI  :  

来源: Delinasios GJ CO

【 摘 要 】

Therapies targeting p53 mostly concentrate on (re)activation of the p53 protein, to further induce apoptosis in cancer cells. In the present investigations, the focus was on the identification of small molecules that block the DNA-binding domain of p53 and thus inhibit its function. Using high-throughput in silico screening of approximately 300,000 compounds, we identified eight putatively interacting with the DNA-binding domain of p53. Subsequently, HCT116 p53 wild-type (p53+/+) and knockout (p53–/–) cells were irradiated with 16 Gy and treated with these compounds. Among the eight compounds, NSC 23175 offered the best protection against γ-irradiation-mediated injury. Microarray-based mRNA expression profiling revealed many downstream p53-dependent genes in irradiated and NSC 23175-treated p53+/+ cells. Using a luciferase reporter assay, we showed that NSC 23175 suppressed p53 binding to the promoter of EGR1, a p53-regulated gene. The fact that NSC 23175 protected p53+/+ cells implicates a putative protective effect of the compound during radiotherapy of p53-mutated tumors. The role of NSC 23175 as protecting agent, in reducing radiotherapy-related side-effects merits future investigation.

【 授权许可】

Unknown