Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis
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Newman_Small-molecule.pdf
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Author(s)
Hiraki, Masatsugu
Hwang, So-Young
Cao, Shugeng
Ramadhar, Timothy R.
Byun, Sanguine
Yoon, Kyoung Wan
Lee, Jung Hyun
Chu, Kiki
Gurkar, Aditi U.
Kolev, Vihren
Date Issued
August 2015
Journal
Chemistry and Biology
Publisher
Elsevier
Citation
Hiraki, Masatsugu; Hwang, So-Young; Cao, Shugeng; Ramadhar, Timothy R.; Byun, Sanguine; Yoon, Kyoung Wan; Lee, Jung Hyun; et al. “Small-Molecule Reactivation of Mutant P53 to Wild-Type-Like P53 through the P53-Hsp40 Regulatory Axis.” Chemistry & Biology 22, no. 9 (September 2015): 1206–1216. © 2015 Elsevier Ltd
Version
Author's final manuscript
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.
MIT Department
Broad Institute of MIT and Harvard
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.chembiol.2015.07.016
