apr-246 has been researched along with 2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one* in 8 studies
1 review(s) available for apr-246 and 2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one
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Prima-1 and APR-246 in Cancer Therapy.
p53 is the most mutated protein in cancer and the reactivation of its inactive mutated form represents one possibility for antitumor therapy. Reactivation leads to the initiation of apoptosis followed by the suppression of the malignant phenotype. Prima-1 and its methylated form Prima-1Met (also called APR-246) are compounds capable of reactivating mutated p53. Both are low-molecular substances that have been tested in a number of tumor cell lines and tumors bearing mutated p53.. This article summarizes what is currently known about both compounds, describes the possibilities of their use in anti-tumor therapy, and outlines the results of currently undergoing clinical trials of APR-246.. The results show that the mechanism of action of both compounds is still not clear. The mechanism is only known clearly in the case of Prima-1, and APR-246 is only known to induce apoptosis. The specificity of both substances for mutated p53 differs considerably and depends mainly on the cell model employed and the type of mutation. In addition to p53 reactivation itself, these compounds likely influence other mechanisms that also affect cytotoxic activity. Key words: Prima-1Met - APR-246 - Prima-1 - reactivation of p53 - apoptosis NPU I - LO1413. This work was supported by the project MEYS - NPS I - LO1413. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 16. 07. 2018. Topics: Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Humans; Neoplasms; Quinuclidines; Tumor Suppressor Protein p53 | 2018 |
7 other study(ies) available for apr-246 and 2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one
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Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).
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 Topics: Antineoplastic Agents; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Crystallography, X-Ray; Humans; Loss of Function Mutation; Neoplasms; Protein Domains; Quinuclidines; Recombinant Proteins; Tumor Suppressor Protein p53 | 2021 |
Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer?
The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1 Topics: Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Mutation; Quinuclidines; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53 | 2017 |
Ranking the Binding Energies of p53 Mutant Activators and Their ADMET Properties.
The guardian of the genome, p53, is the most mutated protein found in all cancer cells. Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. Several molecules have already been found to activate mutant p53. While the exact mechanism of action of these compounds has not been fully understood, a transiently open pocket has been identified in some mutants. In our study, we docked twelve known activators to p53 into the open pocket to further understand their mechanism of action and rank the best binders. In addition, we predicted the absorption, distribution, metabolism, excretion and toxicity properties of these compounds to assess their pharmaceutical usefulness. Our studies showed that alkylating ligands do not all bind at the same position, probably due to their varying sizes. In addition, we found that non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. The comparison of the different ligands demonstrates that stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties. Topics: Alkylation; Amifostine; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Evaluation, Preclinical; Ellipticines; Heterocyclic Compounds, 4 or More Rings; Humans; Kinetics; Ligands; Mercaptoethylamines; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Mutation; Oxepins; Protein Binding; Pyrimidines; Quinuclidines; Tumor Suppressor Protein p53 | 2015 |
PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa.
Targeting p53 by the small-molecule PRIMA-1(Met)/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1(Met)-induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1(Met) alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1(Met) decreased the viability of multiple myeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells. Treatment of multiple myeloma cells with PRIMA-1(Met) resulted in induction of apoptosis, inhibition of colony formation, and migration. PRIMA-1(Met) restored wild-type conformation of mutant p53 and induced activation of p73 upregulating Noxa and downregulating Mcl-1 without significant modulation of p53 level. siRNA-mediated silencing of p53 showed a little effect on apoptotic response of PRIMA-1(Met), whereas knockdown of p73 led to substantial attenuation of apoptotic activity in multiple myeloma cells, indicating that PRIMA-1(Met)-induced apoptosis is, at least in part, p73-dependent. Importantly, PRIMA-1(Met) delayed tumor growth and prolonged survival of mice bearing multiple myeloma tumor. Furthermore, combined treatment of PRIMA-1(Met) with dexamethasone or doxorubicin displayed synergistic effects in both multiple myeloma cell lines and primary multiple myeloma samples. Consistent with our in vitro observations, cotreatment with PRIMA-1(Met) and dexamethasone resulted in enhanced antitumor activity in vivo. Our study for the first time shows antimyeloma activity of PRIMA-1(Met) and provides the rationale for its clinical evaluation in patients with multiple myeloma, including the high-risk group with p53 mutation/deletion. Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Dexamethasone; DNA-Binding Proteins; Doxorubicin; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, SCID; Multiple Myeloma; Neoplasms, Experimental; Nuclear Proteins; Proto-Oncogene Proteins c-bcl-2; Quinuclidines; Tumor Protein p73; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays | 2013 |
PRIMA-1(MET)/APR-246 targets mutant forms of p53 family members p63 and p73.
The low molecular weight compound PRIMA-1 and the structural analog PRIMA-1(MET), also named APR-246, reactivate mutant p53 through covalent binding to the core domain and induce apoptosis in tumor cells. Here, we asked whether PRIMA-1(MET)/APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. We found that PRIMA-1(MET)/APR-246 can restore the pro-apoptotic function to mutant TAp63γ and TAp73β in tumor cells but has less effect on TAp73α. Moreover, PRIMA-1(MET)/APR-246-stimulated DNA binding of mutant TAp63γ and induced expression of the p53/p63/p73 downstream targets p21 and Noxa. The reactivation of mutant p53, p63 and p73 by PRIMA-1(MET)/APR-246 indicates a common mechanism, presumably involving homologous structural elements in the p53 family proteins. Our findings may open avenues for therapeutic intervention in human developmental disorders with mutations in p63. Topics: Antineoplastic Agents; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; DNA-Binding Proteins; Gene Expression; Humans; Mutation; Nuclear Proteins; Proto-Oncogene Proteins c-bcl-2; Quinuclidines; Trans-Activators; Transcription Factors; Tumor Protein p73; Tumor Suppressor Proteins | 2010 |
PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2.
p53 mutations occur frequently in human tumors. The low-molecular-weight compound PRIMA-1(MET) reactivates mutant p53, induces apoptosis in human tumor cells and inhibits tumor xenograft growth in vivo. Here, we show that PRIMA-1(MET) induces mutant p53-dependent mitochondria-mediated apoptosis through activation of caspase-2 with subsequent cytochrome c release and further activation of downstream caspase-9 and caspase-3. Inhibition of caspase-2 by a selective inhibitor and/or siRNA prevents cytochrome c release on PRIMA-1(MET) treatment and causes a significant reduction in PRIMA-1(MET)-induced cell death. Our findings highlight a chain of cellular events triggered by PRIMA-1(MET) that lead to apoptotic cell death. This should facilitate further development and optimization of efficient PRIMA-1(MET)-based anticancer drugs. Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Caspase 2; Caspase 3; Caspase 9; Caspase Inhibitors; Cytochromes c; Drug Evaluation, Preclinical; Enzyme Activation; Enzyme Inhibitors; Genes, p53; Humans; Membrane Potential, Mitochondrial; Mitochondria; Quinuclidines; Tissue Distribution; Tumor Cells, Cultured | 2008 |
PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis.
Mutant p53-carrying tumors are often more resistant to chemotherapeutical drugs. We demonstrate here that the mutant p53-reactivating compound PRIMA-1(MET) acts synergistically with several chemotherapeutic drugs to inhibit tumor cell growth. Combined treatment with cisplatin and PRIMA-1(MET) resulted in a synergistic induction of tumor cell apoptosis and inhibition of human tumor xenograft growth in vivo in SCID mice. The induction of mutant p53 levels by chemotherapeutic drugs is likely to increase the sensitivity of tumor cells to PRIMA-1(MET). Thus, the combination of PRIMA-1(MET) with currently used chemotherapeutic drugs may represent a novel and more efficient therapeutic strategy for treatment of mutant p53-carrying tumors. Topics: Adenocarcinoma; Animals; Apoptosis; Aza Compounds; Bone Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Interactions; Drug Resistance, Neoplasm; Genes, p53; Humans; Lung Neoplasms; Mice; Mice, SCID; Mutation; Osteosarcoma; Quinuclidines; Transplantation, Heterologous; Tumor Cells, Cultured | 2005 |