APR-246 (PRIMA-1MET)

For research use only.

Catalog No.S7724

1 publication

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. APR-246 induces apoptosis and autophagy.

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Selleck's APR-246 (PRIMA-1MET) has been cited by 1 publication

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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. APR-246 induces apoptosis and autophagy.
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 NYfrW5V2S2WubDD2bYFjcWyrdImgZZN{[Xl? MX;obYdpKHOnboPpeIl3cXS7IHHu[EBk\WyuIHTlZZRpKGmwZIXjeIlwdiCrbjDhcIwhXFB3M331eEBt\XWtZX3pZZMtKGK3dDDsc5chSVCULUK0OkB{\W6|aYTpeol1gSCrbjDUVFU{f3RiQVzM NHLsb2U{OTB5M{C3Oi=>
UoCB-6 Mn3NR4VtdCC4aXHibYxqfHliYYPzZZk> MmTtbIlocCC|ZX7zbZRqfmm2eTDhcoQh[2WubDDk[YF1cCCrbnT1Z5Rqd25iaX6gZYxtKFSSNUPteZQhdGW3a3XtbYF{NCCkdYSgcI94KEGSUj2yOFYhe2Wwc3n0bZZqfHliaX6gWHA2O3e2IFHMUC=> NHHQN5Q{OTB5M{C3Oi=>
EU-3 Mo[4R4VtdCC4aXHibYxqfHliYYPzZZk> MV3obYdpKHOnboPpeIl3cXS7IHHu[EBk\WyuIHTlZZRpKGmwZIXjeIlwdiCrbjDhcIwhXFB3M331eEBt\XWtZX3pZZMtKGK3dDDsc5chSVCULUK0OkB{\W6|aYTpeol1gSCrbjDUVFU{f3RiQVzM MV2zNVA4OzB5Nh?=
MUTZ-5 NEf4OVdE\WyuII\pZYJqdGm2eTDhd5NigQ>? NYXDTlV{cGmpaDDz[Y5{cXSrdnn0fUBidmRiY3XscEBl\WG2aDDpcoR2[3Srb36gbY4h[WyuIGTQOVNufXRibHX1b4VucWG|LDDieZQhdG:5IFHQVk0zPDZic3Xud4l1cX[rdImgbY4hXFB3M4f0JGFNVA>? M4GyNFMyODd|MEe2
KOPN-8 Ml;4R4VtdCC4aXHibYxqfHliYYPzZZk> NXPQcG9YcGmpaDDz[Y5{cXSrdnn0fUBidmRiY3XscEBl\WG2aDDpcoR2[3Srb36gbY4h[WyuIGTQOVNufXRibHX1b4VucWG|LDDieZQhdG:5IFHQVk0zPDZic3Xud4l1cX[rdImgbY4hXFB3M4f0JGFNVA>? MnvvN|ExPzNyN{[=
RS4;11 M1y1[2NmdGxidnnhZoltcXS7IHHzd4F6 MVXobYdpKHOnboPpeIl3cXS7IHHu[EBk\WyuIHTlZZRpKGmwZIXjeIlwdiCrbjDhcIwhXFB3M331eEBt\XWtZX3pZZMtKGK3dDDsc5chSVCULUK0OkB{\W6|aYTpeol1gSCrbjDUVFU{f3RiQVzM NVLTXmc{OzFyN{OwO|Y>
SKBR3 MnjHR4VtdCCleXPs[UBie3OjeR?= MlH3OUDDvU1? M2nnXVIhf2Wna4O= M4e2TIxieGG2aX7pZkBqdiClb33ibY5ifGmxbjD3bZRpKEGSUj2yOFYh[2G3c3XkJIEhdG:5ZYKgcIV3\Wxib3[gS|Eh[XK{ZYP0JIFv\CCjbjDpcoNz\WG|ZTDpckB1cGVic4XiMWcyKG[{YXP0bY9v MX6zNFc1Ozl7Nh?=
BT549 M{DGRWNmdGxidnnhZoltcXS7IHHzd4F6 MYfJR|UxRTNwMTFOwG0> MWOzNFE6PjJ|Nh?=
MDA-MB-468 MVzD[YxtKH[rYXLpcIl1gSCjc4PhfS=> NULnV3pzUUN3ME21JO69VQ>? MmKzN|AyQTZ{M{[=
MDA-MB-231 MVrD[YxtKH[rYXLpcIl1gSCjc4PhfS=> MkLvTWM2OD12LkGg{txO NX;iWI57OzBzOU[yN|Y>
HCC1143 MWPD[YxtKH[rYXLpcIl1gSCjc4PhfS=> Ml;3TWM2OD14Lkig{txO NHnWTnE{ODF7NkKzOi=>
MDA-MB-453 M2fWcWNmdGxidnnhZoltcXS7IHHzd4F6 NH;KZppKSzVyPUCuPUDPxE1? M3L6[lMxOTl4MkO2
SKBR3 NIHhZ4ZE\WyuII\pZYJqdGm2eTDhd5NigQ>? NES4NZVKSzVyPUWuNUDPxE1? MmPTN|AyQTZ{M{[=
UACC812 NXLtUZc5S2WubDD2bYFjcWyrdImgZZN{[Xl? NGDRe2pKSzVyPUGxMlMh|ryP NGq5b3Y{ODF7NkKzOi=>
MCF7 MnK1R4VtdCC4aXHibYxqfHliYYPzZZk> M2TDT2lEPTB;M{GuNUDPxE1? Moj4N|AyQTZ{M{[=
MCF10A NYPseIxuS2WubDD2bYFjcWyrdImgZZN{[Xl? NGfnfFFKSzVyPUWuNkDPxE1? M4LCSFMxOTl4MkO2
UMSCC10A MoT2R4VtdCC4aXHibYxqfHliYYPzZZk> NY\sPVR2OC13MDFOwG0> M3WwNFczKGh? NHfm[ZN{fXCycnXzd4VlKGOnbHygd5Vzfmm4YXygZY5lKGKxcnWgZUBud2Snc4Sg[YZn\WO2IH;uJJRp\SCtaXzsbY5oKG:oIFjOV2NEKGOnbHzz MX:yPVM1QDR4Mh?=
FaDu M4W2NWNmdGxidnnhZoltcXS7IHHzd4F6 M3;3XlAuPTBizszN NHfmRYQ4OiCq MXHzeZBxemW|c3XkJINmdGxic4Xyeol3[WxiYX7kJIJwemViYTDtc4Rme3RiZX\m[YN1KG:wIITo[UBscWyuaX7nJI9nKEiQU1PDJINmdGy| NGD1SGkzQTN2OES2Ni=>

... 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]

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  • 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

* 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(C(=O)C2CCN1CC2)CO

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04383938 Recruiting Drug: APR-246 (eprenetapopt) + Pembrolizumab Bladder Cancer|Gastric Cancer|Non Small Cell Lung Cancer|NSCLC|Urothelial Carcinoma|Advanced Solid Tumor Aprea Therapeutics June 25 2020 Phase 1|Phase 2
NCT04214860 Recruiting Drug: APR-246|Drug: Venetoclax|Drug: Azacitidine Myeloid Malignancy Aprea Therapeutics December 13 2019 Phase 1
NCT03745716 Active not 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

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID