Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ)
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In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1 MET) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins.
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Eprenetapopt 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 [22]
The Introduction identifies eprenetapopt as a prodrug converted to MQ and describes MQ as a Michael acceptor that binds p53 cysteine groups. The Abstract reports covalent cysteine binding and stabilization relevant to restoring p53 function, while the Methods call MQ a product spontaneously formed from APR-246. The paper does not specify conversion under physiological conditions or demonstrate a thermodynamic shift in conformational equilibrium. (LLM, conf=0.82)
Experimental — accuracy not yet measuredEprenetapopt 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 [22]
The Introduction identifies eprenetapopt (APR-246) as a clinically advanced mutant-p53 reactivator and describes its active compound, MQ, as disrupting antioxidant systems and depleting glutathione. It also reports apoptosis-related effects in mutant-p53 tumor cells. However, our copy does not describe eprenetapopt as “first-in-class” or report that it induces ferroptosis; it notes that some redox-related cell death is p53-independent. (LLM, conf=0.88)
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- Authors
- Degtjarik, O., Golovenko, D., Diskin-Posner, Y., Abrahmsén, L., Rozenberg, H., & Shakked, Z.
- Affiliations
- Weizmann Institute of Science (IL)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Rozenberg, Haim
- Shakked, Zippora
- Venue
- Nature Communications
- Published
- 2021-12-03
- Volume
- 12
- Issue
- 1
- Pages
- 7057-7057
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8642532
- OpenAlex
- W3217461331
- Cited by
- 78
- References
- 69
- Citations by year
- 2026: 20 · 2025: 14 · 2024: 12 · 2023: 15 · 2022: 17
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Aprea Therapeutics AB. Kimmelman Center for Biomolecular Structure and Assembly (Weizmann Institute of Science).
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- p53, PRIMA-1, APR-246, mutant p53 reactivation, p53 core domain, DNA response elements, tumor suppressor, crystal structure
- MeSH terms
- Protein Domains, Loss of Function Mutation, Antineoplastic Agents, Aza Compounds, Humans, Neoplasms, Quinuclidines, Recombinant Proteins, Tumor Suppressor Protein p53, Crystallography, X-Ray, Bridged Bicyclo Compounds, Heterocyclic
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