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SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations
Ana Sara Gomes1, Helena Ramos1, Sara Gomes1
1LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
Background:
Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1.
Methods And Results:
By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced.
Conclusions:
SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53.
General Significance:
This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.
Insights
SLMP53-1 reactivates wild-type and mutant p53 proteins, offering a promising strategy for personalized cancer therapy. This compound directly targets p53, restoring its tumor-suppressing function in various cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- TP53 mutations inactivate p53, a crucial tumor suppressor, in approximately half of human cancers.
- Reactivating mutant p53 (mutp53) to restore wild-type (wt)-like function is a key therapeutic strategy.
- SLMP53-1, a novel oxazoloisoindolinone, has demonstrated p53-dependent antitumor activity.
Purpose of the Study:
- To elucidate the mechanism by which SLMP53-1 reactivates mutp53.
- To investigate SLMP53-1's ability to target various mutp53 forms.
- To confirm SLMP53-1's therapeutic potential in personalized cancer treatment.
Main Methods:
- Cellular thermal shift assay (CETSA) to assess protein-ligand interactions.
- In silico studies to predict binding sites of SLMP53-1 with p53.
- Yeast and p53-null tumor cell assays to evaluate mutp53 reactivation.
Main Results:
- SLMP53-1 stabilizes both wt and mutp53 R280K, indicating direct binding.
- Computational analysis revealed SLMP53-1 binds to the p53 homodimer-DNA interface.
- SLMP53-1 demonstrated the ability to reactivate multiple prevalent mutp53 forms.
Conclusions:
- SLMP53-1 is a p53-activating agent targeting both wt and hotspot mutp53.
- SLMP53-1 shows promise for personalized cancer therapy based on individual p53 status.
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