This study was conducted to understand the challenges in drugging p53 mutations include heterogeneous mechanisms of inactivation and the absence of broadly applicable allosteric sites. ATO rescues multiple p53 mutants effectively in various assays. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. The researchers exclusively studied the little details of cells and DNA binding for this study. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall β-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Widely applicable, yet has individual p53 mutation-based therapeutic potential.
As a conclusion we can say that all the results that were obtained, provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies. Most p53 mutants are stabilized structurally but only some are transcriptionally rescued.
Reference- https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30605-X
