| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 50mg |
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| 100mg |
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| 250mg | |||
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| Targets |
Checkpoint kinase 1 (Chk1).
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| ln Vitro |
Cells are considerably shielded from the decreased viability following GDC-0425 treatment by inhibiting MEK with medication inhibitors or RNAi-mediated gene silencing [3]. Chk1 becomes hyperphosphorylated after being treated with GDC-0425 (3 μM) for 24 hours [3].
GDC-0425 is a potent and highly selective inhibitor of Chk1. It dose-dependently inhibits the proliferation of Chk1-positive breast cancer cells (0.001-10 mM, 72 h) and induces Chk1 hyperphosphorylation (3 µM, 24 h). Studies indicate that GDC-0425-induced cell death is dependent on the Ras-MEK signaling pathway; blocking this pathway (e.g., with MEK inhibitors or RNAi) protects cells from viability reduction. GDC-0425 enhances the efficacy of gemcitabine in tumor xenograft models. |
| ln Vivo |
Tumor development was partially inhibited by GDC-0425. In every model that was investigated, the gemcitabine/GDC-0425 combination produced a significant tumor regression [3].
In vivo, GDC-0425 (50-75 mg/kg, oral) partially inhibits tumor growth in nude mice bearing osteosarcoma (143B) or triple-negative breast cancer (HCC1806, HCC70) xenografts. When administered 24, 48, and 72 hours after gemcitabine (120 mg/kg, i.p.), GDC-0425 induces significant tumor regression in all models. This demonstrates the potential of GDC-0425 as a chemosensitizer, enhancing the efficacy of DNA-damaging chemotherapy. The compound is orally available and has been investigated in clinical trials for various malignancies. |
| Enzyme Assay |
Chk1 kinase activity is assessed using in vitro biochemical assays. Recombinant Chk1 enzyme is incubated with a peptide substrate and ATP in the presence of varying concentrations of GDC-0425. Kinase activity is measured by quantifying the incorporation of radioactive phosphate (e.g., using 33P-ATP) into the substrate or by using luminescence-based assays (e.g., ADP-Glo). IC50 values are calculated from dose-response curves by nonlinear regression analysis. Selectivity is evaluated by profiling against a panel of kinases.
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| Cell Assay |
Cell Viability Assay[3]
Cell Types: Chk1 Positive Breast Cancer Cell Line Tested Concentrations: 0.001, 0.01, 0.1, 1, 10 mM Incubation Duration: 72 hrs (hours) Experimental Results: diminished cell proliferation. Cell viability assay[3] Cell Types: U-2 OS Cell Tested Concentrations: 3 μM Incubation Duration: 24 hrs (hours) Experimental Results: Causes hyperphosphorylation of Chk1. Cellular activity is evaluated in cancer cell lines, including breast cancer, osteosarcoma, and ovarian cancer cells. Cells are treated with GDC-0425 at various concentrations (typically 0.001-10 µM) for 24-72 hours. Cell proliferation is measured by MTT, MTS, or CellTiter-Glo assays. Chk1 hyperphosphorylation is assessed by Western blot using phospho-specific antibodies. Cell cycle distribution is analyzed by flow cytometry to assess checkpoint abrogation. Apoptosis is measured by caspase-3/7 activation or Annexin V staining. The effect of Ras-MEK pathway modulation on GDC-0425 activity is assessed using MEK inhibitors or RNAi. |
| Animal Protocol |
Animal/Disease Models: NCr nude mice bearing osteosarcoma and triple-negative breast cancer model xenografts (143B PML BK TK, HCC1806 and HCC70 cell lines) [3]
Doses: For 4-arm study, mice were treated with vehicle, gemcitabine 120 mg /kg, GDC-0425 75 mg/kg alone, or gemcitabine and GDC-0425 in combination for 15 days. For the 6-arm study in the HCC1806 and HCC70 models, mice were treated with vehicle alone, gemcitabine 120 mg/kg, GDC-0425 50 mg/kg, GDC-0425 75 mg/kg, or the combination of gemcitabine and GDC-0425. Route of Administration: Gemcitabine is administered orally 24, 48, and 72 hrs (hrs (hours)) after intraperitoneal (ip) injection. Experimental Results: Treatment with gemcitabine or GDC-0425 alone partially inhibited tumor growth. Notably, the gemcitabine/GDC-0425 combination resulted in significant tumor regression in all models tested. In vivo efficacy is studied in mouse xenograft models of cancer, including osteosarcoma (143B) and triple-negative breast cancer (HCC1806, HCC70). GDC-0425 is administered orally at doses of 50-75 mg/kg. Gemcitabine is administered intraperitoneally at 120 mg/kg. GDC-0425 is given 24, 48, and 72 hours after gemcitabine. Tumor growth is measured by caliper twice weekly, and tumor volume is calculated. Tumor regression and growth inhibition are assessed. Pharmacodynamic markers including Chk1 phosphorylation and apoptosis are assessed in tumor tissue. |
| ADME/Pharmacokinetics |
GDC-0425 has a molecular formula of C18H19N5O and a molecular weight of 321.38 g/mol. CAS Number: 1200129-48-1. Appearance: White solid. Purity is typically ≥98% by HPLC. The compound is orally bioavailable. It is soluble in DMSO. Storage: store at -20°C for long-term stability, protected from light and moisture. Detailed pharmacokinetic parameters including half-life, oral bioavailability, and plasma protein binding are available from preclinical and clinical studies.
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| Toxicity/Toxicokinetics |
Safety data for GDC-0425 are available from preclinical and clinical studies. As a Chk1 inhibitor that abrogates cell cycle checkpoints, it may enhance the toxicity of DNA-damaging agents. Common adverse events may include myelosuppression, gastrointestinal toxicity, and fatigue. The compound is for research use only and not for human therapeutic applications without appropriate regulatory approval. Standard laboratory safety practices should be followed during handling, including the use of personal protective equipment and adequate ventilation.
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| References |
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| Additional Infomation |
GDC-0425 is currently undergoing clinical trial NCT01359696 (a study evaluating the safety, tolerability, and pharmacokinetics of GDC-0425 in combination with or without gemcitabine for the treatment of patients with refractory solid tumors or lymphoma). GDC-0425, a Chk1 inhibitor, is an orally bioavailable checkpoint kinase 1 (Chk1) inhibitor with potential antitumor and chemosensitizing activities. After oral administration, GDC-0425 selectively binds to Chk1, thereby inhibiting Chk1 activity and blocking DNA damage repair. This may lead to the accumulation of damaged DNA, inhibition of cell cycle arrest, and induction of apoptosis. GDC-0425 may enhance the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapeutic drugs. Chk1 is an ATP-dependent serine/threonine kinase that mediates cell cycle checkpoint control, is crucial for DNA repair, and plays a key role in resistance to chemotherapeutic drugs.
GDC-0425 (RG-7602) is a research tool compound and clinical candidate for studying Chk1 biology and DNA damage response. It is not approved for clinical use. The compound has been investigated in clinical trials for the treatment of various malignancies, including breast cancer, ovarian cancer, and pancreatic cancer, in combination with DNA-damaging agents like gemcitabine. GDC-0425's ability to abrogate Chk1-mediated cell cycle checkpoints sensitizes cancer cells to DNA-damaging chemotherapy, making it a valuable tool for chemosensitization studies. Its activity is modulated by the Ras-MEK signaling pathway, suggesting that tumors with aberrant Ras-MEK signaling may be particularly sensitive to Chk1 inhibition. |
| Molecular Formula |
C18H19N5O
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|---|---|
| Molecular Weight |
321.384
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| Exact Mass |
321.158
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| CAS # |
1200129-48-1
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| PubChem CID |
58266779
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| Appearance |
Off-white to brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
589.2±50.0 °C at 760 mmHg
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| Flash Point |
310.2±30.1 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.686
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| LogP |
3.82
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
24
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| Complexity |
483
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCN1CCC(CC1)OC2=C3C4=C(NC3=CN=C2C#N)N=CC=C4
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| InChi Key |
XEZLBMHDUXSICI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H19N5O/c1-2-23-8-5-12(6-9-23)24-17-14(10-19)21-11-15-16(17)13-4-3-7-20-18(13)22-15/h3-4,7,11-12H,2,5-6,8-9H2,1H3,(H,20,22)
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| Chemical Name |
3-(1-ethylpiperidin-4-yl)oxy-5,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2,4,6,10,12-hexaene-4-carbonitrile
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| Synonyms |
GDC 0425; GDC-0425; GDC0425
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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) |
H2O : ~25 mg/mL (~77.79 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 | 3.1116 mL | 15.5579 mL | 31.1158 mL | |
| 5 mM | 0.6223 mL | 3.1116 mL | 6.2232 mL | |
| 10 mM | 0.3112 mL | 1.5558 mL | 3.1116 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.
Link: https://clinicaltrials.gov/ct2/show/NCT01359696
Conditions:Solid TumorProducts are for research use only; We do not sell to patients
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