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Description: APR-246 (also known as PRIMA-1MET), a methylated derivative of PRIMA-1 and a mutant p53 reactivator, is a novel and potent small molecule compound that is able to restore wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. It has the potential to treat various human tumor types that are mutant p53-dependent. PRIMA-1 suppressed the growth of Saos-2-His-273 osteosarcoma cell but did not affect the cell lines which express wild type P53. PRIMA-1 directly binds to mutant p53 according to gel shift assay. PRIMA-1MET induced nucleolar translocation of Hsp70, PML, CBP and p53 in MCF 7 cells.
References: Cell Death Dis. 2015 Jun 18;6:e1794; Clin Cancer Res. 2011 May 1;17(9):2830-41.
Related CAS:5608-24-2 (PRIMA-1)
Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2
In vitro activity: APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wild-type conformation. APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. It not only reactivates p53 but also decreases intracellular glutathione levels in a dose-dependent manner. APR-246 can trigger apoptosis in a p53-independent manner by inducing ROS and endoplasmic reticulum (ER) stress and by inhibiting thioredoxin reductase 1 (TrxR1). It was also reported that APR-246 induces cell death in myeloma cells independently of p53 status by impairing the GSH/ROS balance. PRIMA-1Met/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells.
Kinase 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.
Cell Assay: OVCAR-3 cells were plated at a density of 75 000 cells per well in 3 ml of medium in 12-well plates. Next day, 2.5 ml medium was removed and cells were treated with cisplatin or APR-246 or in combination for 20 h. Next day, cells were harvested by trypsinization, washed twice and cells were stained with Annexin V and propidium iodine (PI). After staining, the samples were analyzed by LSRII flow cytometer.
Purity ≥98%
COA
MSDS
Inhibition of TrxR1 in vitro by APR-246. Cell Death Dis. 2013 Oct 24;4:e881.
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.