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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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Multifunctional metallochaperone modifications for targeting subsite cavities in mutant p53-Y220C
Jessica J Miller1, Kalvin Kwan1, Anaïs Blanchet2
1Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, Canada.
Journal of Inorganic Biochemistry
|March 5, 2023
Summary
New small molecules targeting the p53 Y220C mutation show promise. While not reactivating the mutant protein, these compounds induce cancer cell death through reactive oxygen species generation.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- The p53 protein is crucial for cancer prevention, but mutations, like Y220C, compromise its function.
- Over 50% of cancers involve p53 point mutations, creating a need for therapeutic strategies.
- The Y220C mutation unfolds the protein and creates a druggable pocket.
Purpose of the Study:
- To design and synthesize novel small molecules (L5-P, L5-O) as potential zinc metallochaperones and binders for the p53 Y220C mutant.
- To evaluate the efficacy of these new ligands in reactivating mutant p53 and their cytotoxic effects.
- To investigate the mechanism of action and toxicity pathways of the novel ligands.
Main Methods:
- Synthesis of two new bifunctional ligands, L5-P and L5-O, with modified structures compared to a previously reported ligand (L5).
- Assessment of zinc-binding affinity and metallochaperone activity.
- Evaluation of cytotoxicity using NCI-60 cell line screening and a specific Y220C mutant cell line (NUGC3).
- Determination of the primary mechanism of cytotoxicity, including reactive oxygen species (ROS) generation.
Main Results:
- L5-P and L5-O exhibited similar zinc-binding affinity to L5 but were not efficient zinc metallochaperones.
- Both L5-P and L5-O demonstrated significant cytotoxicity in various cancer cell lines, including the Y220C mutant line.
- The primary mechanism for L5-P and L5-O cytotoxicity was identified as reactive oxygen species (ROS) generation, distinct from L5's mechanism of mutant p53 reactivation.
Conclusions:
- Subtle modifications in ligand structure can significantly alter the mechanism of action and therapeutic pathway.
- L5-P and L5-O represent a new class of compounds that induce cancer cell death via ROS generation, offering an alternative strategy to p53 reactivation.
- Further investigation into ROS-generating compounds targeting p53 mutants is warranted for cancer therapy development.
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