Bifunctional ligand design for modulating mutant p53 aggregation in cancer

Autor: Jessica J. Miller, Tim Storr, Christophe Orvain, Anais Blanchet, Diego Martelino, Derek J. Wilson, Lucienne Nouchikian, Ryan M. Clarke, Yasmin Reviriot, Christian Gaiddon
Přispěvatelé: Department of Chemistry [Burnaby, Canada], Simon Fraser University (SFU.ca), Equipe 2 'Réponse au Stress Cellulaire & Thérapies Innovantes' / 'Stress Response & Innovative Therapies' (STREINTH - Inserm U1113), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Chemistry Department [Ontario, Canada], York University [Toronto], Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), This work was supported by a Natural Sciences and Engineering Research Council (NSERC) Discovery Grant and a Michael Smith Career Investigator Award (T. S.). J. J. M. thanks NSERC and SFU for postgraduate fellowships. R. M. C. acknowledges NSERC for a postgraduate fellowship. Prof. Jeffrey Warren is thanked for helpful discussions. Work at the Universit´e de Strasbourg is supported by the CNRS, Inserm, and ARC., Gaiddon, Christian
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Chemical Science
Chemical Science, The Royal Society of Chemistry, 2019, Epub ahead of print. ⟨10.1039/c9sc04151f⟩
Chemical Science, 2019, Epub ahead of print. ⟨10.1039/c9sc04151f⟩
ISSN: 2041-6520
2041-6539
DOI: 10.1039/c9sc04151f⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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