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Bifunctional Ligand Design for Modulating Mutant p53 Aggregation in Cancer

Abstract

Protein misfolding and aggregation contributes to the development of a wide range of diseases. In cancer, over 50% of diagnoses are attributed to p53 malfunction due to missense mutations, many of which result in protein misfolding and accelerated aggregation. p53 mutations also frequently result in alteration or loss of zinc at the DNA-binding site, which increases aggregation via nucleation with zinc-bound p53. Herein, we designed two novel bifunctional ligands, LI and LH, to modulate mutant p53 aggregation and restore zinc binding using a metallochaperone approach. Interestingly, only the incorporation of iodine function in LI resulted in modulation of mutant p53 aggregation, both in recombinant and cellular environments. Native mass spectrometry shows a protein-ligand interaction for LI, as opposed to LH, which is hypothesized to lead to the distinct difference in the p53 aggregation profile for the two ligands. Incorporation of a di-2-picolylamine binding unit into the ligand design provided efficient intracellular zinc uptake, resulting in metallochaperone capability for both LI and LH. The ability of LI to reduce mutant p53 aggregation results in increased restoration of p53 transcriptional function and mediates both caspase-dependent and -independent cell death pathways. We further demonstrate that LI exhibits minimal toxicity in non-cancerous organoids, and that it is well tolerated in mice. These results demonstrate that iodination of our ligand framework restores p53 function by interacting with and inhibiting mutant p53 aggregation and highlights LI as a suitable candidate for comprehensive in vivo anticancer preclinical evaluations.

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Publication details

The article was received on 20 Aug 2019, accepted on 06 Oct 2019 and first published on 07 Oct 2019


Article type: Edge Article
DOI: 10.1039/C9SC04151F
Chem. Sci., 2019, Accepted Manuscript
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Bifunctional Ligand Design for Modulating Mutant p53 Aggregation in Cancer

    J. J. Miller, A. Blanchet, C. Orvain, L. Nouchikian, Y. Reviriot, R. M. Clarke, D. Martelino, D. Wilson, C. Gaiddon and T. Storr, Chem. Sci., 2019, Accepted Manuscript , DOI: 10.1039/C9SC04151F

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