ArticleThe Journal of biological chemistry2010
SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 106 citations in OpenAlex.
- TP53 mutations and MDM2 polymorphisms in breast and ovarian cancers: amelioration by drugs and natural compounds.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Review
- iSoMAs: Finding isoform expression and somatic mutation associations in human cancers.PLoS computational biology · 2025Article
- Review
- Side-stepping the guardian of the genome: current cancer therapeutics targeting mutant p53.Frontiers in pharmacology · 2025Review
- From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.Biomarker research · 2024Review
- Review
- Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy.Cancer communications (London, England) · 2024Review
- Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules.Frontiers in pharmacology · 2024Article
- Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression.International journal of molecular sciences · 2022Article
- Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells.Pharmaceuticals (Basel, Switzerland) · 2022Article
- GOF Mutant p53 in Cancers: A Therapeutic Challenge.Cancers · 2022Review
- Proapoptotic Effect and Molecular Docking Analysis of Curcumin-Resveratrol Hybrids in Colorectal Cancer Chemoprevention.Molecules (Basel, Switzerland) · 2022Article
- Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer.Biomolecules · 2022Review
- Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile.Frontiers in oncology · 2022Article
- Targeting mutant p53 for cancer therapy: direct and indirect strategies.Journal of hematology & oncology · 2021Review
- TP53 in Biology and Treatment of Osteosarcoma.Cancers · 2021Review
- Rapid Evaluation of Small Molecule Cellular Target Engagement with a Luminescent Thermal Shift Assay.ACS medicinal chemistry letters · 2021Article
- Structural and Drug Targeting Insights on Mutant p53.Cancers · 2021Review
- Review
- Regulating tumor suppressor genes: post-translational modifications.Signal transduction and targeted therapy · 2020Review
Corrections and comments
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Abrogation of p53 function occurs in almost all human cancers, with more than 50% of cancers harboring inactivating mutations in p53 itself. Mutation of p53 is indicative of highly aggressive cancers and poor prognosis. The vast majority of mutations in p53 occur in its core DNA binding domain (DBD) and result in inactivation of p53 by reducing its thermodynamic stability at physiological temperature. Here, we report a small molecule, SCH529074, that binds specifically to the p53 DBD in a saturable manner with an affinity of 1-2 microm. Binding restores wild type function to many oncogenic mutant forms of p53. This small molecule reactivates mutant p53 by acting as a chaperone, in a manner similar to that previously reported for the peptide CDB3. Binding of SCH529074 to the p53 DBD is specifically displaced by an oligonucleotide with a sequence derived from the p53-response element. In addition to reactivating mutant p53, SCH529074 binding inhibits ubiquitination of p53 by HDM2. We have also developed a novel variant of p53 by changing a single amino acid in the core domain of p53 (N268R), which abolishes binding of SCH529074. This amino acid change also inhibits HDM2-mediated ubiquitination of p53. Our novel findings indicate that through its interaction with p53 DBD, SCH529074 restores DNA binding activity to mutant p53 and inhibits HDM2-mediated ubiquitination.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.