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

Chem Biol. 2015 Sep 17;22(9):1206-16. doi: 10.1016/j.chembiol.2015.07.016. Epub 2015 Aug 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Disulfides / chemistry
  • Disulfides / pharmacology*
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • HSP40 Heat-Shock Proteins / metabolism*
  • High-Throughput Screening Assays
  • Humans
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / pharmacology*
  • Mice
  • Mice, Nude
  • Mutation
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • DNAJB1 protein, human
  • Disulfides
  • HSP40 Heat-Shock Proteins
  • Indole Alkaloids
  • Small Molecule Libraries
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • chetomin