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Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53

Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
Biomolecules 2020, 10(2), 303; https://doi.org/10.3390/biom10020303 (registering DOI)
Received: 27 January 2020 / Revised: 9 February 2020 / Accepted: 11 February 2020 / Published: 14 February 2020
(This article belongs to the Special Issue Recent Advances in p53)
The mutational landscape of p53 in cancer is unusual among tumor suppressors because most of the alterations are of the missense type and localize to a single domain: the ~220 amino acid DNA-binding domain. Nearly all of these mutations produce the common effect of reducing p53’s ability to interact with DNA and activate transcription. Despite this seemingly simple phenotype, no mutant p53-targeted drugs are available to treat cancer patients. One of the main reasons for this is that the mutations exert their effects via multiple mechanisms—loss of DNA contacts, reduction in zinc-binding affinity, and lowering of thermodynamic stability—each of which involves a distinct type of physical impairment. This review discusses how this knowledge is informing current efforts to develop small molecules that repair these defects and restore function to mutant p53. Categorizing the spectrum of p53 mutations into discrete classes based on their inactivation mechanisms is the initial step toward personalized cancer therapy based on p53 allele status.
Keywords: folding; stability; structure; zinc binding; DNA binding; metallochaperone; aggregation; tumor suppressor; cancer. folding; stability; structure; zinc binding; DNA binding; metallochaperone; aggregation; tumor suppressor; cancer.
MDPI and ACS Style

Loh, S.N. Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53. Biomolecules 2020, 10, 303.

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