APR-246 (PRIMA-1MET)

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 MUfD[YxtKH[rYXLpcIl1gSCjc4PhfS=> M1n2U4hq\2hic3Xud4l1cX[rdImgZY5lKGOnbHyg[IVifGhiaX7keYN1cW:wIHnuJIFtdCCWUEWzcZV1KGyndXvlcYlieyxiYoX0JIxwfyCDUGKtNlQ3KHOnboPpeIl3cXS7IHnuJHRRPTO5dDDBUGw> NU\ZUpRbOzFyN{OwO|Y>
UoCB-6 M1Xh[mNmdGxidnnhZoltcXS7IHHzd4F6 NH\0[ZRpcWeqIIPlcpNqfGm4aYT5JIFv\CClZXzsJIRm[XSqIHnu[JVkfGmxbjDpckBidGxiVGC1N412fCCuZYXr[Y1q[XNuIHL1eEBtd3diQWDSMVI1PiC|ZX7zbZRqfmm2eTDpckBVWDV|d4SgRWxN M3\pcVMyODd|MEe2
EU-3 NIPleW1E\WyuII\pZYJqdGm2eTDhd5NigQ>? NECzZVNpcWeqIIPlcpNqfGm4aYT5JIFv\CClZXzsJIRm[XSqIHnu[JVkfGmxbjDpckBidGxiVGC1N412fCCuZYXr[Y1q[XNuIHL1eEBtd3diQWDSMVI1PiC|ZX7zbZRqfmm2eTDpckBVWDV|d4SgRWxN M2TRelMyODd|MEe2
MUTZ-5 MmTtR4VtdCC4aXHibYxqfHliYYPzZZk> M3HlXYhq\2hic3Xud4l1cX[rdImgZY5lKGOnbHyg[IVifGhiaX7keYN1cW:wIHnuJIFtdCCWUEWzcZV1KGyndXvlcYlieyxiYoX0JIxwfyCDUGKtNlQ3KHOnboPpeIl3cXS7IHnuJHRRPTO5dDDBUGw> M4DhSFMyODd|MEe2
KOPN-8 MYXD[YxtKH[rYXLpcIl1gSCjc4PhfS=> NX:5W4ZScGmpaDDz[Y5{cXSrdnn0fUBidmRiY3XscEBl\WG2aDDpcoR2[3Srb36gbY4h[WyuIGTQOVNufXRibHX1b4VucWG|LDDieZQhdG:5IFHQVk0zPDZic3Xud4l1cX[rdImgbY4hXFB3M4f0JGFNVA>? M3G2fVMyODd|MEe2
RS4;11 NWDlfFY6S2WubDD2bYFjcWyrdImgZZN{[Xl? MlyxbIlocCC|ZX7zbZRqfmm2eTDhcoQh[2WubDDk[YF1cCCrbnT1Z5Rqd25iaX6gZYxtKFSSNUPteZQhdGW3a3XtbYF{NCCkdYSgcI94KEGSUj2yOFYhe2Wwc3n0bZZqfHliaX6gWHA2O3e2IFHMUC=> MlTsN|ExPzNyN{[=
SKBR3 NVfx[HZRS2WubDDjfYNt\SCjc4PhfS=> NEHzRZI2KML3TR?= MljFNkB4\WWtcx?= MonFcIFx[XSrbnniJIlvKGOxbXLpcoF1cW:wIIfpeIghSVCULUK0OkBk[XW|ZXSgZUBtd3encjDs[ZZmdCCxZjDHNUBienKnc4SgZY5lKGGwIHnuZ5Jm[XOnIHnuJJRp\SC|dXKtS|Eh\nKjY4Tpc44> MYSzNFc1Ozl7Nh?=
BT549 MUjD[YxtKH[rYXLpcIl1gSCjc4PhfS=> Mn7aTWM2OD1|LkGg{txO NXvnXGx{OzBzOU[yN|Y>
MDA-MB-468 NVfQcIw6S2WubDD2bYFjcWyrdImgZZN{[Xl? NUG4NFVtUUN3ME21JO69VQ>? MWqzNFE6PjJ|Nh?=
MDA-MB-231 MY\D[YxtKH[rYXLpcIl1gSCjc4PhfS=> MoTWTWM2OD12LkGg{txO MlHxN|AyQTZ{M{[=
HCC1143 NXnFcoQ2S2WubDD2bYFjcWyrdImgZZN{[Xl? NH7YbItKSzVyPU[uPEDPxE1? NITUUFY{ODF7NkKzOi=>
MDA-MB-453 MWLD[YxtKH[rYXLpcIl1gSCjc4PhfS=> MY\JR|UxRTBwOTFOwG0> MVezNFE6PjJ|Nh?=
SKBR3 M2DBNmNmdGxidnnhZoltcXS7IHHzd4F6 NI\LVlZKSzVyPUWuNUDPxE1? MmqyN|AyQTZ{M{[=
UACC812 MUTD[YxtKH[rYXLpcIl1gSCjc4PhfS=> MkXjTWM2OD1zMT6zJO69VQ>? M4jZdlMxOTl4MkO2
MCF7 NWDt[nNkS2WubDD2bYFjcWyrdImgZZN{[Xl? MmLZTWM2OD1|MT6xJO69VQ>? NV;hb25SOzBzOU[yN|Y>
MCF10A MX7D[YxtKH[rYXLpcIl1gSCjc4PhfS=> NVvTVII3UUN3ME21MlIh|ryP M1O0WVMxOTl4MkO2
UMSCC10A M1fSXGNmdGxidnnhZoltcXS7IHHzd4F6 MorqNE02OCEQvF2= MYq3NkBp NHrJTVd{fXCycnXzd4VlKGOnbHygd5Vzfmm4YXygZY5lKGKxcnWgZUBud2Snc4Sg[YZn\WO2IH;uJJRp\SCtaXzsbY5oKG:oIFjOV2NEKGOnbHzz NFrobJAzQTN2OES2Ni=>
FaDu Mn7HR4VtdCC4aXHibYxqfHliYYPzZZk> MViwMVUxKM7:TR?= NUfFVGdSPzJiaB?= NH;DO4N{fXCycnXzd4VlKGOnbHygd5Vzfmm4YXygZY5lKGKxcnWgZUBud2Snc4Sg[YZn\WO2IH;uJJRp\SCtaXzsbY5oKG:oIFjOV2NEKGOnbHzz MXqyPVM1QDR4Mh?=

... 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
  • Formulation: PBS
  • 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

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03745716 Recruiting Drug: APR-246 + azacitidine|Drug: Azacitidine MDS Aprea Therapeutics AB January 11 2019 Phase 3
NCT03391050 Terminated Drug: APR-246|Drug: Dabrafenib Melanoma Aprea Therapeutics AB|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
NCT00900614 Completed Drug: APR-246 Hematologic Neoplasms|Prostatic Neoplasms Aprea Therapeutics AB May 2009 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID