Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis

Masatsugu Hiraki, So Young Hwang, Shugeng Cao, Timothy R. Ramadhar, Sanguine Byun, Kyoung Wan Yoon, Jung Hyun Lee, Kiki Chu, Aditi U. Gurkar, Vihren Kolev, Jianming Zhang, Takushi Namba, Maureen E. Murphy, David J. Newman, Anna Mandinova, Jon Clardy, Sam W. Lee

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36 Citations (Scopus)

Abstract

Summary TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant.

Original languageEnglish
Pages (from-to)1206-1216
Number of pages11
JournalChemistry and Biology
Volume22
Issue number9
DOIs
Publication statusPublished - 2015 Sep 17

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    Hiraki, M., Hwang, S. Y., Cao, S., Ramadhar, T. R., Byun, S., Yoon, K. W., Lee, J. H., Chu, K., Gurkar, A. U., Kolev, V., Zhang, J., Namba, T., Murphy, M. E., Newman, D. J., Mandinova, A., Clardy, J., & Lee, S. W. (2015). Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis. Chemistry and Biology, 22(9), 1206-1216. https://doi.org/10.1016/j.chembiol.2015.07.016