[HTML][HTML] Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism

X Yu, AR Blanden, S Narayanan, L Jayakumar… - Oncotarget, 2014 - ncbi.nlm.nih.gov
X Yu, AR Blanden, S Narayanan, L Jayakumar, D Lubin, D Augeri, SD Kimball, SN Loh
Oncotarget, 2014ncbi.nlm.nih.gov
Abstract NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration
of WT structure/function to the most common p53 missense mutant (p53-R175H). We
investigated the mechanism by which ZMC1 reactivates p53-R175H and provide evidence
that ZMC1: 1) restores WT structure by functioning as a zinc-metallochaperone, providing an
optimal concentration of zinc to facilitate proper folding; and 2) increases cellular reactive
oxygen species that transactivate the newly conformed p53-R175H (via post-translational …
Abstract
NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure/function to the most common p53 missense mutant (p53-R175H). We investigated the mechanism by which ZMC1 reactivates p53-R175H and provide evidence that ZMC1: 1) restores WT structure by functioning as a zinc-metallochaperone, providing an optimal concentration of zinc to facilitate proper folding; and 2) increases cellular reactive oxygen species that transactivate the newly conformed p53-R175H (via post-translational modifications), inducing an apoptotic program. We not only demonstrate that this zinc metallochaperone function is possessed by other zinc-binding small molecules, but that it can reactivate other p53 mutants with impaired zinc binding. This represents a novel mechanism for an anti-cancer drug and a new pathway to drug mutant p53.
Significance: We have elucidated a novel mechanism to restore wild-type structure/function to mutant p53 using small molecules functioning as zinc-metallochaperones. The pharmacologic delivery of a metal ion to restore proper folding of a mutant protein is unique to medicinal chemistry and represents a new pathway to drug mutant p53.
ncbi.nlm.nih.gov