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Purity: ≥98%
Eprenetapopt (APR-246; PRIMA-1MET), a methylated PRIMA-1 derivative and mutant p53 reactivator, is a brand-new and powerful small molecule drug that can restore mutant p53's wild-type conformation and function while also inducing apoptosis in tumor cells. It has the potential to treat different p53-dependent human tumor types. While having no effect on cell lines expressing wild-type P53, PRIMA-1 inhibited the growth of Saos-2-His-273 osteosarcoma cells. According to a gel shift assay, PRIMA-1 directly binds to mutant p53. Hsp70, PML, CBP, and p53 were all nucleolarly translocated in MCF 7 cells by PRIMA-1MET. Eprenetapopt was recently described as a ferroptosis inducer with anticancer properties.
| Targets |
p53 activator; TrxR1 inhibitor
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| ln Vitro |
APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is transformed into the active ingredient methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and returns it to its wild-type conformation. Drug-resistant ovarian cancer cells with p53 mutations are completely restored to cisplatin and doxorubicin sensitivity by APR-246. Along with reactivating p53, it also dose-dependently lowers intracellular glutathione levels. By increasing ROS and ER stress, inhibiting thioredoxin reductase 1 (TrxR1), and inducing ROS and ER stress, APR-246 can cause apoptosis in a p53-independent manner. Additionally, it was noted that APR-246 alters the GSH/ROS balance in myeloma cells, causing cell death regardless of p53 status[1]. In vitro, PRIMA-1Met/APR-246 effectively stopped the growth of SCLC cell lines expressing mutant p53. It also caused apoptosis, which is characterized by an increase in the proportion of DNA-fragmented cells, caspase-3 activation, PARP cleavage, upregulation of Bax and Noxa, and downregulation of Bcl-2 in the cells[2].
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| ln Vivo |
APR-246 demonstrated a favorable safety profile in a Phase I/II clinical dose-finding study on prostate cancer and hematological malignancies, and both clinical and p53-dependent biological responses were noted. APR-246 is well tolerated in studies on animals. When mice with the fast-growing A2780-CP20 tumor xenografts are given just one dose of APR-246, the tumor size is reduced by 21%[1].
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| Enzyme Assay |
Cells are plated in six-well plates at a density of 15 000 cells per cm2. Next day, cells are treated with different concentrations of APR-246 (0, 25, 50, 75 and 100 μM) and harvested after 4, 12 and 24 h. The cells are lysed, and the clarified supernatants are used for either analysis of TrxR enzymatic activities or western blot. Total protein concentrations are determined with a Bradford reagent kit. Cellular TrxR activity is measured using an adapted Trx-dependent end point insulin reduction assay for microwell plates.
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| Cell Assay |
In 12-well plates, 3 ml of medium and 75 000 OVCAR-3 cells were plated per well. The cells were treated for 20 hours with cisplatin, APR-246, or both the following day after 2.5 ml of the medium had been removed. The following day, cells were collected by trypsinization, twice-washed, and stained with Annexin V and propidium iodine (PI). The samples were stained, and then the LSRII flow cytometer was used to analyze them.
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| Animal Protocol |
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| References | |||
| Additional Infomation |
Eprenetapopt has been used in trials studying the treatment of Prostatic Neoplasms, Hematologic Neoplasms, and Platinum Sensitive Recurrent High-grade Serous Ovarian Cancer With Mutated p53.
Eprenetapopt is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis), with potential antineoplastic activity. Upon administration, eprenetapopt covalently modifies the core domain of mutated forms of cellular tumor antigen p53 (p53) through the alkylation of thiol groups. These modifications restore both the wild-type conformation and function to mutant p53, which reconstitutes endogenous p53 activity, leading to cell cycle arrest and apoptosis in tumor cells. This agent may work synergistically with other antineoplastic agents. p53, a tumor suppressor and transcription factor normally activated upon DNA damage, is frequently mutated and overexpressed in cancer cells; it plays a key role in both DNA repair and the induction of apoptosis. |
| Molecular Formula |
C10H17NO3
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| Molecular Weight |
199.25
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| Exact Mass |
199.12
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| Elemental Analysis |
C, 60.28; H, 8.60; N, 7.03; O, 24.09
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| CAS # |
5291-32-7
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| Related CAS # |
PRIMA-1;5608-24-2
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| PubChem CID |
52918385
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
313.8±17.0 °C at 760 mmHg
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| Flash Point |
143.6±20.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.537
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| LogP |
0.61
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
14
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| Complexity |
236
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C2([H])C([H])([H])C([H])([H])N(C([H])([H])C2([H])[H])C1(C([H])([H])O[H])C([H])([H])OC([H])([H])[H]
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| InChi Key |
BGBNULCRKBVAKL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C10H17NO3/c1-14-7-10(6-12)9(13)8-2-4-11(10)5-3-8/h8,12H,2-7H2,1H3
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| Chemical Name |
2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (12.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (12.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (12.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (501.88 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.0188 mL | 25.0941 mL | 50.1882 mL | |
| 5 mM | 1.0038 mL | 5.0188 mL | 10.0376 mL | |
| 10 mM | 0.5019 mL | 2.5094 mL | 5.0188 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04990778 | Withdrawn | Drug: Eprenetapopt Drug: Venetoclax |
Recurrent Mantle Cell Lymphoma Refractory Mantle Cell Lymphoma |
M.D. Anderson Cancer Center | November 30, 2021 | Phase 2 |
Inhibition of TrxR1in vitroby APR-246.Cell Death Dis.2013 Oct 24;4:e881. |
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siRNA knockdown of TrxR1 inhibits APR-246-induced cell death.Cell Death Dis.2013 Oct 24;4:e881. |
siRNA knockdown of TrxR1 inhibits generation of ROS induced by treatment with APR-246.Cell Death Dis.2013 Oct 24;4:e881. |
Inhibition of TrxR1 activity in living cells.Cell Death Dis.2013 Oct 24;4:e881. |
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