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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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Bifunctional ligand design for modulating mutant p53 aggregation in cancer
Jessica J Miller1, Anaïs Blanchet2, Christophe Orvain2
1Department of Chemistry , Simon Fraser University , Burnaby , British Columbia V5A 1S6 , Canada .
Chemical Science
|February 15, 2020
Summary
Researchers developed a novel ligand (L) that reduces mutant p53 aggregation, restoring its function and mediating cancer cell death. This promising compound shows minimal toxicity and is a candidate for preclinical anticancer evaluations.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Protein misfolding and aggregation are implicated in numerous diseases, including cancer.
- Mutant p53 protein, found in over 50% of cancer diagnoses, often misfolds, aggregates, and loses zinc, promoting tumorigenesis.
- Metallochaperone strategies offer a potential therapeutic approach to address mutant p53 dysfunction.
Purpose of the Study:
- To design and evaluate novel bifunctional ligands for modulating mutant p53 aggregation and restoring zinc binding.
- To investigate the role of ligand structure, specifically iodine incorporation, in p53 aggregation modulation.
- To assess the therapeutic potential of the developed ligands as anticancer agents.
Main Methods:
- Design and synthesis of two novel bifunctional ligands (L and L) incorporating a di-2-picolylamine unit for zinc uptake.
- Utilizing native mass spectrometry to analyze protein-ligand interactions.
- Assessing ligand efficacy in modulating mutant p53 aggregation in recombinant and cellular models.
- Evaluating restoration of p53 transcriptional activity and induction of cancer cell death.
- Testing ligand toxicity in non-cancerous organoids and in vivo mouse models.
Main Results:
- Ligand L, containing iodine, effectively modulated mutant p53 aggregation in both recombinant and cellular environments, unlike L.
- Native mass spectrometry confirmed protein-ligand interaction for L, correlating with its aggregation modulation.
- Both ligands demonstrated metallochaperone capability, facilitating intracellular zinc uptake.
- L treatment reduced mutant p53 aggregation, restored p53 transcriptional function, and induced cancer cell death via caspase-dependent and -independent pathways.
- L exhibited minimal toxicity in organoids and was well-tolerated in mice.
Conclusions:
- Iodination of the ligand framework is crucial for modulating mutant p53 aggregation.
- Ligand L acts as a metallochaperone, inhibiting mutant p53 aggregation and restoring tumor suppressor function.
- Ligand L shows significant promise as an anticancer therapeutic candidate for further preclinical evaluation.
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