product name PRIMA-1
Description: PRIMA-1 [2,2-Bis(hydroxymethyl)-3-quinuclidinone], a novel small molecule compound which is the active form of APR-246 (also known as PRIMA-1MET), is a mutant p53 reactivator which induces apoptosis and inhibits growth of human tumors. PRIMA-1 rescues the tumor-suppressing function of mutant p53 proteins and shows anti-tumor activity in vivo. P53 severs as a crucial tumor suppressor and mutant p53 is expressed at high levels in many tumors. PRIMA-1 is considered as a lead compound for the development of anticancer drugs targeting mutant p53.
References: Invest New Drugs. 2014 Oct;32(5):783-94; Cancer Cell. 2009 May 5;15(5):376-88; Nat Med. 2002 Mar;8(3):282-8.
185.22
Formula
C9H15NO3
CAS No.
5608-24-2
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 37 mg/mL (199.8 mM)
Water: 37 mg/mL (199.8 mM)
Ethanol:
Solubility (In vivo)
Synonyms
2,2-Bis(hydroxymethyl)-3-quinuclidinone
other peoduct :
| In Vitro |
In vitro activity: PRIMA-1 is converted to compounds that form adducts with thiols in mutant p53. Modification of thiol groups in mutant p53 by PRIMA-1 conversion products is sufficient to restore its tumor suppressor activity. PRIMA-1 inhibits the growth of pancreatic cancer cell lines and induces cell cycle arrest and decreases DNA synthesis. It selectively induces apoptosis and cell death in mutant p53-expressing pancreatic cancer cells and also leads to activation of p53-dependent apoptotic pathways. PRIMA-1 enhances the cytotoxicity of chemotherapeutic agents active against mutant p53 pancreatic cancer cells. PRIMA-1 has antileukemic properties in acute promyelocytic leukemia-derived NB4 cells. PRIMA-1-triggered apoptosis is in a dose-dependent and time-dependent manner as indicated by the MTT assay and annexin-V staining. Apoptosis induction by PRIMA-1 is associated with caspase-9, caspase-7 activation and PARP cleavage. PRIMA-1 does not show any significant apoptotic effect in normal human peripheral blood mononuclear cells. Kinase Assay: Cell Assay: Cells [mutant p53 expressing pancreatic cancer cell lines PANC-1 (p.R273H) and BxPC-3 (p.Y220C) and the wild type p53-expressing Capan-2 cells (wtp53)] are kept at a temperature of 37 °C, a minimum relative humidity of 95 %, and an atmosphere of 5 % CO2 in air. Cell viability is measured by MTT assay after treatment with PRIMA-1. Briefly, cells are seeded in each well of 96-well plates in 100 μl culture medium and incubated overnight at 37 °C in an atmosphere of 5 % CO2. The next day, the medium is removed and cells washed with PBS and treated with vehicle control(DMSO, dimethylsulfoxide) or different concentrations of PRIMA-1 for 12 to 48 h; the medium is replaced with MTT solution diluted in medium once the treatment is completed. The plates are further incubated at 37 °C under 5 % CO2 for 4 h and then left at room temperature until completely dry. DMSO was then added and the absorbance is read at 492 nm using a microplate enzyme-linked immunoassay reader (ELISA). The relative growth activity is determined as the percentage absorbance of treated cells compared to that of vehicle treated cells (control). |
|---|---|
| In Vivo | PRIMA-1 (Prima-1) is a p53-modulating agent. 150 or 300 ppm PRIMA-1 significantly suppresses (P < 0.0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Administration of 150 or 300 ppm PRIMA-1 significantly suppresses NNK-induced total lung adenocarcinoma formation by 57% or 62% (P<0.0001), respectively, after 17 weeks of exposure and by 39% or 56% (P < 0.0001), respectively, after 34 weeks of exposure. As with administration of the lower (50 ppm) dose of CP-31398, administration of the lower (150 ppm) dose of PRIMA-1also slightly increases the number of NNK-induced lung adenomas.
Intravenous (i.v.) injections of PRIMA-1 in mice does not cause any obvious changes in weight or behavior compared with untreated animals. PRIMA-1 has in vivo antitumor activity in this animal tumor model. It suppresses in vivo tumor growth in a mutant p53-dependent manner. |
| Animal model | SCID mice |
| Formulation & Dosage | Dissolved in PBS; 1, 10, 20 and 100 mg/kg; i.v. injection |
| References | Invest New Drugs. 2014 Oct;32(5):783-94; Cancer Cell. 2009 May 5;15(5):376-88; Nat Med. 2002 Mar;8(3):282-8; Neoplasia. 2013 Sep;15(9):1018-27. |
