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| Targets |
p53 DBD (Ki = 1-2 μM)
SCH529074 targets the interaction between MDM2 (mouse double minute 2 homolog) and p53, a key tumor suppressor protein. MDM2 is an E3 ubiquitin ligase that binds to p53 and promotes its degradation. By binding to MDM2 and blocking this interaction, SCH529074 stabilizes p53, leading to its accumulation and activation of p53-mediated transcriptional programs, including cell cycle arrest and apoptosis. |
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| ln Vitro |
In p53 mutant cells (H157, H1975, and H322), SCH529074 (2-4 μM; 24 hours) significantly reduced cell viability, to 20–25%, and in the p53 WT cell line A549, to 68 % 4 μM. In NSCLC cells (H157, A549, HCT116, and HCT116 p53-/-), SCH 529074 (2 and 4 μM) induces G0/G1 phase when compared to control cells treated with low concentration (2 μM) (59). 72%, 66%, 57%, and 57%[1]. H1975 cells are exposed to SCH 529074 (2-4 μM) for 24 hours, which causes both early and late fluorescence. Similar to how SCH 529074 at 2 and 4 μM greatly boosted early and late cells in A549 cells, it also considerably enhanced H157 cells. This is supported by the fact that SCH 529074 at 4 μM significantly promoted early and late cells in HCT116 cells in arc cells, as well as early cells in HCT116 p53-/- cells [1]. SCH 529074 (2–6 μM; 24 hours) raises p21 and PUMA protein levels in wireline
In vitro, SCH529074 binds to MDM2 with high affinity, displacing p53 from the MDM2-p53 complex. This leads to the stabilization of p53 and the induction of p53 target genes, such as p21 and PUMA. It has been shown to inhibit the growth of various cancer cell lines with wild-type p53, while having less effect on cells with mutant p53. |
| ln Vivo |
At dosages of 50 and 30 mg/kg, respectively, of the lung cancer medication SCH529074, tumor development was reduced by 79% and 43% over the course of four weeks, beginning on day three and ending on day thirty-one. In human DLD-1 colorectal cancer xenografts, the degree of inhibition corresponds with the compound's switch sensitivity (0.26-0.55 μM at 30 mg/kg, 0.39-0.79 μM at 50 mg/kg, final 2 post-
In vivo, SCH529074 has been studied in xenograft mouse models of cancer. In these models, oral administration of SCH529074 has been shown to inhibit tumor growth and to induce apoptosis in tumor tissues. The antitumor activity is correlated with the induction of p53 target genes, confirming the mechanism of action. |
| Enzyme Assay |
The in vitro receptor binding assay for SCH529074 involves measuring its affinity for MDM2. This is typically done using a fluorescence polarization (FP) or surface plasmon resonance (SPR) assay, where the binding of SCH529074 to recombinant MDM2 protein is measured. Competition binding experiments with a labeled p53 peptide are performed to determine the IC50.
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| Cell Assay |
cell viability assay [1]
Cell Types: p53 mutant cells (H157, H1975, and H322) and p53 WT cell line A549 Tested Concentrations: 4 or 6 μM, regardless of their p53 status [1]. 2μM; 4 μM Incubation Duration: 24 hrs (hours) Experimental Results: Inhibition of cancer WT and mutant cell viability. Cell cycle analysis[1] Cell Types: H1975, H157, A549, HCT116, HCT116 p53-/- Cell Tested Concentrations: 2 µM, 4 µM, 6 µM Incubation Duration: 24 hrs (hours) Experimental Results: Induced cells in all NSCLC cell lines evaluated apoptotic, regardless of their p53 mutation status. Western Blot Analysis[1] Cell Types: H1975, H322, H157, A549, HCT116, HCT116 p53-/- Tested Concentrations: 2 µM, 4 µM, 6 µM Incubation Duration: 24 hrs (hours) Experimental Results: Increased PUMA and p21 protein expression. In vitro cellular assays for SCH529074 are performed on cancer cell lines with wild-type p53. Cells are treated with SCH529074, and the induction of p53 and its target genes (e.g., p21, PUMA, MDM2) is measured by Western blot or qPCR. Cell cycle analysis and apoptosis assays (annexin V/PI staining) are also performed to assess the functional consequences. |
| Animal Protocol |
Animal/Disease Models: Female nude mice, 5-7 weeks old, were inoculated subcutaneously (sc) (sc) with DLD-1 human colorectal cancer cells [2].
Doses: 30 or 50 mg/kg. Route of Administration: oral; -12 hrs (hrs (hours))) [2]. twice (two times) daily; 4 weeks; starting on day 3 through day 31 Experimental Results: Inhibition of tumor growth In vivo animal experiments for SCH529074 are conducted in xenograft mouse models. Human cancer cells (e.g., HCT116 colon cancer or SJSA-1 osteosarcoma) are implanted subcutaneously into immunodeficient mice. SCH529074 is administered orally, and tumor volume is measured over time to assess its antitumor efficacy. |
| ADME/Pharmacokinetics |
Specific pharmacokinetic properties of SCH529074 are not extensively documented in the available literature. As a small molecule designed for oral administration, it is expected to have reasonable oral bioavailability and to be metabolized in the liver. Its half-life and volume of distribution would be determined in preclinical studies.
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| Toxicity/Toxicokinetics |
Specific toxicity data for SCH529074 are not readily available in the public domain, as it is primarily a research compound. Its toxicity is likely to be related to its mechanism of action, which involves the activation of p53. While p53 activation is desirable in cancer cells, it can cause toxicity in normal tissues, particularly in the bone marrow and gastrointestinal tract.
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| References |
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| Additional Infomation |
N'-(2-{4-[bis-(4-chlorophenyl)methyl]piperazin-1-ylmethyl}quinazolin-4-yl)-N,N-dimethylpropane-1,3-diamine is a potent and orally effective p53 activator. SCH529074 specifically and conformationally binds to the DNA-binding domain (DBD) of p53 in a saturated manner with a Ki value of 1-2 μM. SCH529074 restores the function of mutant p53 and blocks HDM2-mediated ubiquitination of wild-type p53. SCH529074 can be used in research on non-small cell lung cancer (NSCLC). (MedChemExpress)
SCH529074 is a research tool used to study the p53 pathway. It is not an FDA-approved drug. It is one of several MDM2 inhibitors that have been developed as potential anticancer agents. MDM2 inhibitors are a promising class of drugs for the treatment of cancers with wild-type p53, and several have entered clinical trials. |
| Molecular Formula |
C31H36CL2N6
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|---|---|
| Molecular Weight |
563.571
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| Exact Mass |
562.238
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| Elemental Analysis |
C, 66.07; H, 6.44; Cl, 12.58; N, 14.91
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| CAS # |
922150-11-6
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| Related CAS # |
922150-11-6
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| PubChem CID |
12001922
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
6.156
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
39
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| Complexity |
681
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC(C(N2CCN(CC3N=C(NCCCN(C)C)C4C(=CC=CC=4)N=3)CC2)C2C=CC(Cl)=CC=2)=CC=1
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| InChi Key |
NCAJLQDPTZBGJV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H36Cl2N6/c1-37(2)17-5-16-34-31-27-6-3-4-7-28(27)35-29(36-31)22-38-18-20-39(21-19-38)30(23-8-12-25(32)13-9-23)24-10-14-26(33)15-11-24/h3-4,6-15,30H,5,16-22H2,1-2H3,(H,34,35,36)
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| Chemical Name |
N-[2-[[4-[bis(4-chlorophenyl)methyl]piperazin-1-yl]methyl]quinazolin-4-yl]-N',N'-dimethylpropane-1,3-diamine
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| Synonyms |
SCH-529074; SCH529074; SCH 529074
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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 |
| 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: ~20 mg/mL (~35.5 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (1.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1 mg/mL (1.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7744 mL | 8.8720 mL | 17.7440 mL | |
| 5 mM | 0.3549 mL | 1.7744 mL | 3.5488 mL | |
| 10 mM | 0.1774 mL | 0.8872 mL | 1.7744 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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