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| Targets |
p53 tumor suppressor protein, specifically mutant p53 forms (R175H, R248W, R273H). P53R3 binds to mutant p53 and restores its ability to bind DNA in a sequence-specific manner. It also enhances the recruitment of wild-type p53 and p53 M237I to target gene promoters, thereby reactivating p53-dependent transcriptional programs.
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| ln Vitro |
In WiDr colon cancer cells harbouring p53R273H and KLE cells with p53R175H, P53R3 (10 μg/ml; 24 hours; in the absence or presence of the unlabelled p53 consensus oligonucleotide) restores p53-specific DNA binding activity to p53R273H (a DNA contact mutant) and p53R175H (a structural mutant)[1]. In a p53-dependent manner, P53R3 (1–33 μg/ml; 24 hours) prevents the LN-308 sublines carrying mutant p53 plasmids from proliferating. While p53R273H-dependent effects are less and necessitate high concentrations of P53R3, p53R175H-dependent effects are significant across a wide concentration range[1]. Proliferation inhibition caused by P53R3 is more pronounced than that of P53R273H when it comes to p53R248W reactivation. Not even at concentrations near its solubility limit (33 μg/ml) does P53R3 show cytotoxic effects[1]. In LN-308 p53R175H and LN-308 p53R273H cells, P53R3 (33 μg/ml; 18 hours) causes a significant reduction in S phase cells and a G0/G1 cell cycle arrest. However, it had no effect on the LN-308 p53R248W cells' cell cycle distribution[1].
In vitro, P53R3 effectively restores sequence-specific DNA binding to p53 hot spot mutants, including p53 R175H, p53 R248W, and p53 R273H. It enhances the recruitment of wild-type p53 and p53 M237I to several target gene promoters. P53R3 strongly enhances the mRNA, total protein, and cell surface expression of the death receptor DR5 (death receptor 5). It specifically induces p53-dependent antiproliferative effects with much higher specificity than PRIMA-1. |
| ln Vivo |
In vivo activity data for P53R3 are limited in the available literature. Based on its potent in vitro reactivation of mutant p53 and induction of p53-dependent antiproliferative effects, the compound is expected to exhibit antitumor efficacy in appropriate in vivo models. Further studies are needed to evaluate its pharmacokinetic properties and therapeutic potential in animal models of p53-mutant cancers.
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| Enzyme Assay |
p53 DNA binding activity is assessed using electrophoretic mobility shift assays (EMSA) or chromatin immunoprecipitation (ChIP) with wild-type or mutant p53 proteins. The compound is incubated with p53 protein and a DNA probe containing a p53 response element. Restoration of sequence-specific DNA binding is detected by the formation of a shifted complex. Target gene promoter recruitment is evaluated by ChIP-qPCR in p53-expressing cells treated with P53R3.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: p53 null LN -308 human glioma cells with a control plasmid or plasmids encoding the mutants p53R175H, p53R248W and p53R273H Tested Concentrations: 1-33 μg/mL Incubation Duration: 24 hrs (hours) Experimental Results: Induced p53-dependent and -independent antiproliferative and cytotoxic effects in vitro. p53-mutant cancer cell lines (e.g., harboring R175H, R248W, or R273H mutations) are cultured and treated with P53R3 at varying concentrations. Cell viability and proliferation are assessed by CellTiter-Glo or MTT assays. DR5 expression is measured by qRT-PCR and Western blot. Cell surface DR5 is detected by flow cytometry. Apoptosis is assessed by Annexin V/PI staining and caspase activity assays. Comparisons with PRIMA-1 are performed to evaluate specificity. |
| Animal Protocol |
Specific in vivo protocols for P53R3 are not yet established. Standard approaches for evaluating p53 reactivators would involve xenograft models using p53-mutant human cancer cell lines in immunodeficient mice. The compound would be administered orally or intraperitoneally at doses determined from pharmacokinetic studies. Tumor growth inhibition, p53 target gene expression, and apoptosis markers would be assessed.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic parameters for P53R3 are not fully characterized. The compound has molecular formula C32H35Cl2N5O2, molecular weight 592.56, and CAS number 922150-12-7. It shows good solubility in DMSO. Its oral bioavailability, half-life, and tissue distribution require further investigation in preclinical pharmacokinetic studies.
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| Toxicity/Toxicokinetics |
No comprehensive toxicity data are currently available for P53R3. As a research-grade p53 reactivator, its safety profile has not been extensively characterized. Standard preclinical toxicology studies would be necessary to evaluate its safety margin. The compound is generally well-tolerated in vitro at effective concentrations based on available cell-based assays.
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| References | |
| Additional Infomation |
P53R3 is a research-grade small molecule for p53 reactivation studies in cancer research. It restores sequence-specific DNA binding to p53 hot spot mutants (R175H, R248W, R273H) and induces p53-dependent antiproliferative effects with higher specificity than PRIMA-1. The compound enhances DR5 expression and promotes apoptosis. It is for research use only and has not entered clinical trials or received FDA approval. Purity is typically >98%.
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| Molecular Formula |
C32H35CL2N5O2
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| Molecular Weight |
592.55860543251
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| Exact Mass |
591.216
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| CAS # |
922150-12-7
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| PubChem CID |
58809185
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| Appearance |
White to off-white solid powder
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| LogP |
7.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
41
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| Complexity |
790
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C(OC)(=O)[C@H](C(C)C)NC1=C2C(=NC(CN3CCN(C(C4=CC=C(Cl)C=C4)C4=CC=C(Cl)C=C4)CC3)=N1)C=CC=C2
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| InChi Key |
DFBRKGUTHGRQMH-LJAQVGFWSA-N
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| InChi Code |
InChI=1S/C32H35Cl2N5O2/c1-21(2)29(32(40)41-3)37-31-26-6-4-5-7-27(26)35-28(36-31)20-38-16-18-39(19-17-38)30(22-8-12-24(33)13-9-22)23-10-14-25(34)15-11-23/h4-15,21,29-30H,16-20H2,1-3H3,(H,35,36,37)/t29-/m0/s1
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| Chemical Name |
methyl (2S)-2-[[2-[[4-[bis(4-chlorophenyl)methyl]piperazin-1-yl]methyl]quinazolin-4-yl]amino]-3-methylbutanoate
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (168.76 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6876 mL | 8.4380 mL | 16.8759 mL | |
| 5 mM | 0.3375 mL | 1.6876 mL | 3.3752 mL | |
| 10 mM | 0.1688 mL | 0.8438 mL | 1.6876 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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