APR-246 (PRIMA-1MET)

For research use only.

Catalog No.S7724

APR-246 (PRIMA-1MET) Chemical Structure

Molecular Weight(MW): 199.25

APR-246, also known as PRIMA-1MET, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types.

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Biological Activity

Description APR-246, also known as PRIMA-1MET, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types.
Targets
Mutant p53 [2]
()
In 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 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[1]. 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[2].

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
NALM-6 NEPqbIxE\WyuII\pZYJqdGm2eTDhd5NigQ>? M{\l[Yhq\2hic3Xud4l1cX[rdImgZY5lKGOnbHyg[IVifGhiaX7keYN1cW:wIHnuJIFtdCCWUEWzcZV1KGyndXvlcYlieyxiYoX0JIxwfyCDUGKtNlQ3KHOnboPpeIl3cXS7IHnuJHRRPTO5dDDBUGw> MXGzNVA4OzB5Nh?=
UoCB-6 NGrZTodE\WyuII\pZYJqdGm2eTDhd5NigQ>? M1r0cYhq\2hic3Xud4l1cX[rdImgZY5lKGOnbHyg[IVifGhiaX7keYN1cW:wIHnuJIFtdCCWUEWzcZV1KGyndXvlcYlieyxiYoX0JIxwfyCDUGKtNlQ3KHOnboPpeIl3cXS7IHnuJHRRPTO5dDDBUGw> MkjON|ExPzNyN{[=
EU-3 MVPD[YxtKH[rYXLpcIl1gSCjc4PhfS=> M2LNdohq\2hic3Xud4l1cX[rdImgZY5lKGOnbHyg[IVifGhiaX7keYN1cW:wIHnuJIFtdCCWUEWzcZV1KGyndXvlcYlieyxiYoX0JIxwfyCDUGKtNlQ3KHOnboPpeIl3cXS7IHnuJHRRPTO5dDDBUGw> M4TXclMyODd|MEe2
MUTZ-5 MmS0R4VtdCC4aXHibYxqfHliYYPzZZk> NVL0NZNEcGmpaDDz[Y5{cXSrdnn0fUBidmRiY3XscEBl\WG2aDDpcoR2[3Srb36gbY4h[WyuIGTQOVNufXRibHX1b4VucWG|LDDieZQhdG:5IFHQVk0zPDZic3Xud4l1cX[rdImgbY4hXFB3M4f0JGFNVA>? NULQNVdNOzFyN{OwO|Y>
KOPN-8 M4\4WmNmdGxidnnhZoltcXS7IHHzd4F6 M1Gw[Yhq\2hic3Xud4l1cX[rdImgZY5lKGOnbHyg[IVifGhiaX7keYN1cW:wIHnuJIFtdCCWUEWzcZV1KGyndXvlcYlieyxiYoX0JIxwfyCDUGKtNlQ3KHOnboPpeIl3cXS7IHnuJHRRPTO5dDDBUGw> NUSx[WpKOzFyN{OwO|Y>
RS4;11 NULzd3hsS2WubDD2bYFjcWyrdImgZZN{[Xl? NYfZb|ZncGmpaDDz[Y5{cXSrdnn0fUBidmRiY3XscEBl\WG2aDDpcoR2[3Srb36gbY4h[WyuIGTQOVNufXRibHX1b4VucWG|LDDieZQhdG:5IFHQVk0zPDZic3Xud4l1cX[rdImgbY4hXFB3M4f0JGFNVA>? M3WwRVMyODd|MEe2
SKBR3 NIrMfnJE\WyuIHP5Z4xmKGG|c3H5 MUO1JOK2VQ>? NGX6RVMzKHenZXvz NITVfVBt[XCjdHnubYIhcW5iY3;tZolv[XSrb36ge4l1cCCDUGKtNlQ3KGOjdYPl[EBiKGyxd3XyJIxmfmWuIH;mJGcyKGG{cnXzeEBidmRiYX6gbY5kemWjc3WgbY4hfGinIIP1Zk1IOSCocnHjeIlwdg>? MljlN|A4PDN7OU[=
BT549 M13uV2NmdGxidnnhZoltcXS7IHHzd4F6 MojiTWM2OD1|LkGg{txO MnjPN|AyQTZ{M{[=
MDA-MB-468 MWjD[YxtKH[rYXLpcIl1gSCjc4PhfS=> M3;6eWlEPTB;NTFOwG0> NYXYZmh{OzBzOU[yN|Y>
MDA-MB-231 Mmr4R4VtdCC4aXHibYxqfHliYYPzZZk> M1fhbGlEPTB;ND6xJO69VQ>? Mki3N|AyQTZ{M{[=
HCC1143 MoPJR4VtdCC4aXHibYxqfHliYYPzZZk> MYfJR|UxRTZwODFOwG0> M3PC[|MxOTl4MkO2
MDA-MB-453 NUK4WHdxS2WubDD2bYFjcWyrdImgZZN{[Xl? NGPYcpZKSzVyPUCuPUDPxE1? NUnmRoQ2OzBzOU[yN|Y>
SKBR3 NVTIU|ZES2WubDD2bYFjcWyrdImgZZN{[Xl? MXzJR|UxRTVwMTFOwG0> NX75NYtPOzBzOU[yN|Y>
UACC812 M4\RfGNmdGxidnnhZoltcXS7IHHzd4F6 NVPzRlFiUUN3ME2xNU4{KM7:TR?= NYXjW4tsOzBzOU[yN|Y>
MCF7 NEfpdG1E\WyuII\pZYJqdGm2eTDhd5NigQ>? NHPNSHRKSzVyPUOxMlEh|ryP NUL6dpFxOzBzOU[yN|Y>
MCF10A MnXMR4VtdCC4aXHibYxqfHliYYPzZZk> M4D0XWlEPTB;NT6yJO69VQ>? NXHSRo57OzBzOU[yN|Y>
UMSCC10A NWLGT5hCS2WubDD2bYFjcWyrdImgZZN{[Xl? MkDYNE02OCEQvF2= NFPmW4U4OiCq NYDtXZN5e3WycILld5Nm\CClZXzsJJN2en[rdnHsJIFv\CCkb4LlJIEhdW:mZYP0JIVn\mWldDDvckB1cGVia3nscIlv\yCxZjDIUnNESyClZXzsdy=> NUm1N2V4Ojl|NEi0OlI>
FaDu NYi4RlJjS2WubDD2bYFjcWyrdImgZZN{[Xl? M4XWPFAuPTBizszN NXX2WnFMPzJiaB?= M17vfJN2eHC{ZYPz[YQh[2WubDDzeZJ3cX[jbDDhcoQh[m:{ZTDhJI1w\GW|dDDl[oZm[3Rib36geIhmKGurbHzpcochd2ZiSF7TR2Mh[2WubIO= MUCyPVM1QDR4Mh?=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
FL-PARP / Cleaved PARP ; 

PubMed: 26452133     


PARP cleavage was detected by western blotting analysis after treated with PRIMA-1(met) at different concentrations for 24 hours. 

p-p53; 

PubMed: 26452133     


Phosphorylation of p53 level was determined after PRIMA-1(met) treatment.

26452133
Growth inhibition assay
Cell viability; 

PubMed: 26452133     


A panel of CRC cell lines was treated with either DMSO control or PRIMA-1(met) at indicated dosages for 48 hours, followed by CTG assays. The percentage of cell growth inhibition was normalized with respective DMSO control. 

26452133
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[1].

Protocol

Cell Research:

[1]

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  • Cell lines: OVCAR-3 cells
  • Concentrations: 40 μM
  • Incubation Time: 20 h
  • Method:

    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. 


    (Only for Reference)
Animal Research:

[1]

- Collapse
  • Animal Models: CD-1 Nu/Nu mice
  • Dosages: 400 mg/kg/day
  • Administration: i.v.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 40 mg/mL (200.75 mM)
Water 40 mg/mL (200.75 mM)
Ethanol 40 mg/mL (200.75 mM)

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 199.25
Formula

C10H17NO3

CAS No. 5291-32-7
Storage powder
in solvent
Synonyms N/A
Smiles COCC1(CO)N2CCC(CC2)C1=O

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04383938 Not yet recruiting Drug: APR-246 (eprenetapopt) + Pembrolizumab Bladder Cancer|Gastric Cancer|Non Small Cell Lung Cancer|NSCLC|Urothelial Carcinoma|Advanced Solid Tumor Aprea Therapeutics July 2020 Phase 1|Phase 2
NCT04214860 Recruiting Drug: APR-246|Drug: Venetoclax|Drug: Azacitidine Myeloid Malignancy Aprea Therapeutics December 13 2019 Phase 1
NCT03745716 Recruiting Drug: APR-246 + azacitidine|Drug: Azacitidine MDS Aprea Therapeutics January 11 2019 Phase 3
NCT03391050 Terminated Drug: APR-246|Drug: Dabrafenib Melanoma Aprea Therapeutics|Jules Bordet Institute January 18 2018 Phase 1|Phase 2
NCT02999893 Suspended Drug: APR-246 Oesophageal Carcinoma Peter MacCallum Cancer Centre Australia April 11 2017 Phase 1|Phase 2

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID