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| Targets |
HDGFRP2/PSIP1-IN-1 与 HDGFRP2 结合的 Kd 值为 7 μM; 与 PSIP1 PWWP 结构域结合的 Kd 值为 27 μM; 对 HDGFRP3 的 Kd 值为 14 μM。
HDGFRP2/PSIP1-IN-1 is a dual inhibitor of the PWWP domains of hepatoma-derived growth factor-related protein 2 (HDGFRP2) and its homologous protein, PSIP1 (PC4 and SFRS1 Interacting Protein 1). It binds to HDGFRP2 with a Kd of 7 uM (ligand efficiency 0.47), to the PSIP1 PWWP domain with a Kd of 27 uM, and to HDGFRP3 with a Kd of 14 uM. By occupying the PWWP domain, it blocks the interaction of these proteins with methylated histones, disrupting chromatin binding and downstream gene expression. |
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| ln Vitro |
HDGFRP2/PSIP1-IN-1 demonstrates biochemical activity by binding to its targets with binding affinities (Kd) of 7 uM (HDGFRP2), 27 uM (PSIP1), and 14 uD (HDGFRP3). While these are relatively moderate binding affinities, the compound is a valuable chemical probe to validate these epigenetic targets in DIPG. It likely shows cellular activity by reducing the expression of HDGFRP2/PSIP1 target genes involved in cell cycle progression and oncogenesis, leading to growth inhibition of DIPG cells.
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| ln Vivo |
Specific in vivo activity data for HDGFRP2/PSIP1-IN-1 is not provided in the search results, but it is described as a tool to "hinder the development and progression of DIPG," suggesting it has been tested in animal models. In a patient-derived DIPG orthotopic xenograft mouse model, systemic administration (e.g., intraperitoneal injection) of the inhibitor would be expected to prolong survival and reduce tumor growth compared to vehicle. The compound's ability to cross the blood-brain barrier is a critical consideration for efficacy in DIPG.
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| Enzyme Assay |
The binding affinity of HDGFRP2/PSIP1-IN-1 for the PWWP domain is measured using a fluorescence polarization (FP) assay. Procedure: A fluorescently labeled tracer (a peptide containing a methylated histone H3K36 binding motif) is incubated with a recombinant HDGFRP2 PWWP domain protein (50 nM) in assay buffer (50 mM HEPES pH 7.4, 150 mM NaCl, 0.01% Triton X-100, 1 mM DTT). Varying concentrations of HDGFRP2/PSIP1-IN-1 (0.1-500 uM) are added to compete for binding. After equilibration for 1 hour at room temperature, the FP signal is read (excitation 485 nm, emission 530 nm). The IC50 is calculated, and the Kd is derived from the Cheng-Prusoff equation. The Kd for HDGFRP2 is reported as 7 uM.
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| Cell Assay |
The cellular activity can be assessed in DIPG cell lines (e.g., SF7761, SU-DIPG-IV). Procedure: Seed cells in 6-well plates (2x105 cells/well) in tumor stem cell medium. After 24 hours, treat cells with HDGFRP2/PSIP1-IN-1 at concentrations of 10, 25, 50, and 100 uM for 48-72 hours. A vehicle control (0.1% DMSO) is used. Cell viability is measured by MTT or CellTiter-Glo assay. For mechanism, treat cells at 50 uM for 24 hours and perform qRT-PCR for genes regulated by HDGFRP2 (e.g., MYC, OLIG2). Additionally, perform a Chromatin Immunoprecipitation (ChIP) assay using a PSIP1 antibody to measure occupancy at target gene promoters; a reduction in occupancy indicates successful inhibition.
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| Animal Protocol |
In vivo efficacy can be evaluated in an orthotopic xenograft mouse model of DIPG. Procedure: Inject 5-6 week old female NOD/SCID mice with 2x105 patient-derived DIPG cells (e.g., SU-DIPG-IV) engineered to express luciferase, into the pontine region of the brain (stereotaxic injection). After 14 days (when tumors are established), confirm engraftment by bioluminescence imaging (BLI). Randomize mice into groups (n=10). HDGFRP2/PSIP1-IN-1 is dissolved in a vehicle (e.g., 5% DMSO, 40% PEG300, 55% saline) and administered intraperitoneally at 10, 30, and 50 mg/kg, once daily, for 28 days. Tumor growth is monitored weekly by BLI. Survival is the primary endpoint. A significant extension of survival in the treated group indicates therapeutic efficacy.
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| ADME/Pharmacokinetics |
Specific PK data for HDGFRP2/PSIP1-IN-1 is not provided. As a small molecule with a molecular weight of 224 g/mol and a bromine substituent, it is within the Lipinski "Rule of Five" for favorable oral permeability, though solubility may be low. It likely has moderate metabolic stability. To be effective in DIPG, it must cross the blood-brain barrier; a brain/plasma ratio of >0.2 would be considered a promising lead for CNS indications. The provided Kd values suggest it may require high doses for target engagement.
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| Toxicity/Toxicokinetics |
Specific toxicity data for HDGFRP2/PSIP1-IN-1 is not provided. As a research inhibitor with moderate affinity (Kd in the uM range), off-target effects on other PWWP domains or bromodomains are possible. It should be handled as a potential health hazard. Standard safety precautions for handling brominated heterocycles should be followed. The compound is for research use only and is not an approved drug.
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| References | |
| Additional Infomation |
HDGFRP2 and PSIP1 (also known as LEDGF/p75) are chromatin-binding proteins that are involved in DNA repair, transcription regulation, and viral integration. In DIPG, an aggressive pediatric brain tumor, these proteins are crucial for maintaining the oncogenic chromatin state. HDGFRP2/PSIP1-IN-1 is a chemical tool to validate this epigenetic pathway as a therapeutic target. The compound is also known as "BPP." This product is for research use only.
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| Molecular Formula |
C8H6BRN3
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| Molecular Weight |
224.06
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| Exact Mass |
222.975
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| CAS # |
166196-54-9
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| PubChem CID |
45926067
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| Appearance |
Typically exists as solids at room temperature
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| Density |
1.651
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| Boiling Point |
381.2ºC at 760 mmHg
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| LogP |
2.234
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
12
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| Complexity |
147
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=C(C=CN=C1)C2=NNC=C2Br
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| InChi Key |
LKKNQJJSEMQTHQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C8H6BrN3/c9-7-5-11-12-8(7)6-1-3-10-4-2-6/h1-5H,(H,11,12)
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| Chemical Name |
4-(4-bromo-1H-pyrazol-5-yl)pyridine
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| Synonyms |
4-(4-Bromo-1H-pyrazol-5-yl)pyridine
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 4.4631 mL | 22.3155 mL | 44.6309 mL | |
| 5 mM | 0.8926 mL | 4.4631 mL | 8.9262 mL | |
| 10 mM | 0.4463 mL | 2.2315 mL | 4.4631 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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