APR-246 reactivates mutant p53 by targeting cysteines 124 and 277
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Abstract
The TP 53 tumor suppressor gene is frequently inactivated in human tumors by missense mutations in the DNA binding domain. TP 53 mutations lead to protein unfolding, decreased thermostability and loss of DNA binding and transcription factor function. Pharmacological targeting of mutant p53 to restore its tumor suppressor function is a promising strategy for cancer therapy. The mutant p53 reactivating compound APR-246 (PRIMA-1 Met ) has been successfully tested in a phase I/IIa clinical trial. APR-246 is converted to the reactive electrophile methylene quinuclidinone (MQ), which binds covalently to p53 core domain. We identified cysteine 277 as a prime binding target for MQ in p53. Cys277 is also essential for MQ-mediated thermostabilization of wild-type, R175H and R273H mutant p53, while both Cys124 and Cys277 are required for APR-246-mediated functional restoration of R175H mutant p53 in living tumor cells. These findings may open opportunities for rational design of novel mutant p53-targeting compounds.
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Eprenetapopt is a novel, first-in-class small molecule that reactivates p53 and targets cellular redox balance, inducing apoptosis and ferroptosis in mTP53 cancer cells.
“Eprenetapopt (APR‐246) is a novel, first‐in‐class small molecule that reactivates p53 and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in mTP53 cancer cells.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [21]
The Introduction describes APR-246 as reactivating mutant p53 and disrupting cellular redox balance through thioredoxin reductase inhibition and glutathione depletion. The Results report APR-246-induced apoptosis in cells expressing R175H mutant p53. The paper does not establish that APR-246 induces ferroptosis or that it is first-in-class; its mention of ferroptosis concerns p53 generally. (LLM, conf=0.90)
Experimental — accuracy not yet measuredEprenetapopt is a prodrug converted to methylene quinuclidinone, which covalently binds cysteine residues in mutant p53, stabilizing p53 and shifting equilibrium toward functional conformation.
“Eprenetapopt is a prodrug that, under physiological conditions, is spontaneously converted to methylene quinuclidinone, a Michael acceptor that covalently binds to cysteine residues in mutant p53, leading to thermodynamic stabilization of the p53 protein and shifting the equilibrium toward a functional conformation.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [21]
The Introduction states that APR-246 is converted to MQ, a Michael acceptor that reacts with cysteines in the p53 core domain. The Results and Discussion report MQ-mediated thermostabilization and refolding of mutant p53 toward a wild-type conformation. Our copy does not establish that conversion is spontaneous under physiological conditions or explicitly describe a shift in conformational equilibrium. (LLM, conf=0.87)
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- Authors
- Zhang, Q., Bykov, V. J. N., Wiman, K. G., & Zawacka-Pankau, J.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Wiman, Klas G.
- Venue
- Cell Death & Disease
- Published
- 2018-04-18
- Volume
- 9
- Issue
- 5
- Pages
- 439-439
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5906465
- OpenAlex
- W2951449583
- Cited by
- 261
- References
- 40
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 28 · 2023: 30 · 2022: 42 · 2021: 50 · 2020: 33 · 2019: 20 · 2018: 11
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-10-10)
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Åke Wiberg Stiftelse
- Consortium for History of Science, Technology and Medicine
- Cancerfonden
- Karolinska Institutet
- Vetenskapsrådet
- Radiumhemmets Forskningsfonder
- Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- APR-246, PRIMA-1MET, mutant p53 reactivation, TP53, covalent binding, p53 DNA-binding domain, cancer therapy
- MeSH terms
- Protein Domains, Aza Compounds, Cysteine, Humans, Tumor Suppressor Protein p53, Bridged Bicyclo Compounds, Heterocyclic, Amino Acid Substitution, Mutation, Missense, Cell Line, Tumor, Protein Stability
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