Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics

Cancers
Samuel Kogan, Darren R Carpizo

Abstract

Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as "reactivating" mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are currently developing a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs) and, here, we review our current understanding of them. The p53 protein requires the binding of a single zinc ion, coordinated by four amino acids in the DNA binding domain, for proper structure and function. Loss of the wild-type structure by impairing zinc binding is a common mechanism of inactivating p53. ZMCs reactivate mutant p53 using a novel two-part mechanism that involves restoring the wild-type structure by reestablishing zinc binding and activating p53 through post-translational modifications induced by cellular reactive oxygen species (ROS). The former causes a wild-type conformation change, the later induces a p53-mediated apoptotic program to kill the cancer cell. ZMCs are small molecule metal ion chelators that bind zinc and other divalent metal ions strong enough to remove zinc from serum albumin, but weak enough to donate it to ...Continue Reading

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Citations

Mar 25, 2020·Biomolecules·Silvia Di Agostino
Oct 30, 2019·Mini Reviews in Medicinal Chemistry·Bhushan Shakya, Paras Nath Yadav
May 13, 2020·Archives of Toxicology·Christos T ChasapisMaria E Stefanidou
May 20, 2020·Frontiers in Oncology·Marina SerraAlessio Menga
Mar 13, 2019·Cancers·Natalia Issaeva
Aug 14, 2020·International Journal of Molecular Sciences·Daisy L WongMartin J Stillman

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Methods Mentioned

BETA
acetylation
protein folding
xenograft

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