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

doi:10.1016/j.chembiol.2015.07.016

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.

Authors

Masatsugu Hiraki¹, So-Young Hwang¹, Shugeng Cao², Timothy R Ramadhar³, Sanguine Byun¹, Kyoung Wan Yoon¹, Jung Hyun Lee¹, Kiki Chu¹, Aditi U Gurkar¹, Vihren Kolev¹, Jianming Zhang¹, Takushi Namba¹, Maureen E Murphy⁴, David J Newman⁵, Anna Mandinova⁶, Jon Clardy⁷, Sam W Lee⁸

Affiliations

¹ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
² Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA.
⁵ Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁶ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁷ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jon_clardy@hms.harvard.edu.
⁸ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: swlee@mgh.harvard.edu.

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding