APR-246 (Eprenetapopt), also known as PRIMA-1MET, is a quinuclidinone derivative that targets the Wrap53 gene with potential antineoplastic activity. APR-246 (PRIMA-1MET) enhances apoptosis in mutant p53 carrying cells, compared to the p53 null parental cells. Most p53 mutants are in complex with Hsp70 proteins. PRIMA-1MET treatment increases Hsp70 expression and nucleolar translocation, in parallel with the induction of nucleolar accumulation of mutant p53. Several lines of evidence suggest that PRIMA-1MET can also act independently of the p53 status of the cell.
In animal studies, APR-246 (Eprenetapopt) is well tolerated, APR-246 single treatment inhibits tumor growth by 21% in mice bearing the aggressively growing A2780-CP20 tumor xenografts.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO ≥ 30 mg/mL
Water ≥ 30 mg/mL
APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells
N Mohell, et al. Cell Death Dis. 2015 Jun 18;6(6):e1794. PMID: 26086967.
APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase
X Peng, et al. Cell Death Dis. 2013 Oct 24;4(10):e881. PMID: 24157875.
PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53
Roza Zandi, et al. Clin Cancer Res. 2011 May 1;17(9):2830-41. PMID: 21415220.
PRIMA-1MET induces nucleolar translocation of Epstein-Barr virus-encoded EBNA-5 protein
Gyorgy Stuber, et al. Mol Cancer. 2009 Mar 26;8:23. PMID: 19323829.
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