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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations
Yigang Tang1, Huaxin Song1, Zhengyuan Wang1
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations.
Insights
Scientists repurposed the antiparasitic drug potassium antimony tartrate (PAT) to stabilize temperature-sensitive tumor suppressor p53 (mutant protein) in cancer cells. This approach shows promise for targeted cancer therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The tumor suppressor p53 is frequently inactivated by diverse mutations in cancer.
- Developing targeted therapies to restore p53 function is crucial for cancer treatment.
Purpose of the Study:
- To identify compounds that can pharmacologically rescue temperature-sensitive (TS) p53 mutations.
- To evaluate the potential of repurposed drugs for precision cancer therapy.
Main Methods:
- Rational drug screening using thermostability of TS p53 mutants as a readout.
- Identification and characterization of drug candidates targeting p53 mutations.
- Antitumor activity assessment in xenograft mouse models and patient-derived leukemia cells.
Main Results:
- Potassium antimony tartrate (PAT), an antiparasitic drug, was identified to noncovalently stabilize a TS p53 mutant (p53-V272M).
- PAT demonstrated antitumor activity in vivo and specifically rescued p53-V272M in patient-derived leukemia cells at therapeutic antimony doses.
- 65 out of 815 frequent p53 missense mutations were identified as potentially treatable with PAT.
Conclusions:
- Repurposing noncovalent antiparasitic antimonials like PAT offers a strategy for precision cancer treatment.
- This approach provides a foundation for developing targeted therapies for cancers harboring specific p53 mutations.
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