Thiosemicarbazones Functioning as Zinc Metallochaperones to Reactivate Mutant p53

Thiosemicarbazones Functioning as Zinc Metallochaperones to Reactivate Mutant p53.

Small-molecule restoration of wild-type structure and function to mutant p53 (so-called mutant reactivation) is a highly sought-after goal in cancer drug development. We previously discovered that small-molecule zinc chelators called zinc metallochaperones (ZMCs) reactivate mutant p53 by restoring zinc binding to zinc-deficient p53 mutants. The lead compound identified from the NCI-60 human tum...

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

UNLABELLED 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...

Mutant p53 succumbs to starvation

While the wild type form of p53 possesses strong tumor-suppressive activities, the p53 proteins that are commonly mutated in cancer often endow more malignant properties to the cancers they inhabit. There are several lines of evidence supporting such oncogenic gain of function of mutant p53. Compared with p53-null mice, knock-in mice harboring mutant p53 proteins display different and more meta...

Thiosemicarbazones as New Antitumor Compounds

The search of new compounds with medicinal applications is promoting important therapeutic advances and generates a new scientific multidisciplinary field where chemistry, pharmacy and biomedicine overlap together with other specialities. Thiosemicarbazones are some of the studied compounds. These sulfur-containing organic substances exhibit an interesting biological activity, which has been st...

Structure-Based Design of Molecules to Reactivate Tumor-Derived p53 Mutations