product name APR-246 (PRIMA-1MET)
Description: APR-246, also known as PRIMA-1MET which is a methylated derivative of PRIMA-1, is a small molecule compound that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. 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.
199.25
Formula
C10H17NO3
CAS No.
5291-32-7
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: >10mg/mL
Water:
Ethanol:
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
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: 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. |
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| In Vivo | APR-246 showed a good safety profile in a Phase I/II clinical dose-finding study on hematological malignancies and prostate cancer and both clinical and p53-dependent biological responses were observed. In animal studies, APR-246 is well tolerated. Single treatment with APR-246 inhibits tumor growth by 21% in mice bearing the aggressively growing A2780-CP20 tumor xenografts |
| Animal model | CD-1 Nu/Nu mice |
| Formulation & Dosage | Dissolved in PBS; 400 mg/kg/day; i.v. injection |
| References | Cell Death Dis. 2015 Jun 18;6:e1794; Clin Cancer Res. 2011 May 1;17(9):2830-41. |
