| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Purity: ≥98%
| Targets |
CHK1 (checkpoint kinase 1)
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| ln Vitro |
CCT245737 is a potent inhibitor of recombinant human CHK1 with IC50 of 1.4±0.3 nM (mean±SD, n = 3, EZ Reader II assay). There is > 1,000-fold selectivity for CHK1 versus the functionally important kinases CDK1 and CHK2 (IC50=1.26-2.44 and 9.03 μM, respectively), and at least a 90-fold selectivity against cross-reacting kinases such as ERK8, PKD1, RSK1 and 2. CCT245737 potently inhibits cellular CHK1 activity (IC50 30-220nM) and enhances gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. It can abrogate an etoposide-induced G2/M arrest. CCT245737 has high cell permeability, as measured by transport across a CaCo2 cell monolayer.
Kinase Assay: CCT245737 shows<50% 10= 121= inhibition= at= m= for= representing= a= selectivity= chk1= of=>5000-fold over these enzymes. Commercial in vitro 33P radiometric kinase assays are carried out against 124 human kinases using 10 μM CCT245737 at ATP concentrations corresponding to the kinase Km, ATP. Other kinase IC50 determinations for CHK2 and FLT3 are performed using a commercial assay or in-house with recombinant human CHK1 on a LabChip® EZ Reader II or CDK1 in a DELFIA assay. Cell Assay: Cytotoxicity is determined as the drug concentration that gave 50% inhibition of tumor cell proliferation (GI50) using a 96h (i.e. 4-doublings) Sulforhodamine B (SRB) assay. Inhibition of intracellular CHK1 activity is measured using a cell based ELISA for the abrogation of an etoposide induced G2 checkpoint (mitosis induction assay, MIA). Potently inhibits recombinant human CHK1 with an enzymatic IC50 of 1.4 nM and exhibits greater than 1,000-fold selectivity over CHK2 and CDK1. The compound also potently inhibits cellular CHK1 activity with IC50 values ranging from 30 to 220 nM across multiple human tumor cell lines. |
| ln Vivo |
Mouse oral bioavailability is complete (100%) with extensive tumor exposure. CCT245737 shows significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. An i.v. dose of 10mg/kg CCT245737 into BALB/c mice gives a peak plasma concentration of 4μmol/L, with a half-life of 2.86h, an AUC0-∞ of 9.96μmol.h/L, a plasma clearance of 2.1L/h/kg and a large volume of distribution (0.19L). The equivalent oral dose gave an almost identical profile with an AUC0-∞ of 10.4μmol.h/L showing complete oral bioavailability (F = 105%). In a word, CCT245737 shows complete oral bioavailability with linear pharmacokinetics and high tumor/plasma ratios consistent with extensive tumor exposure. Adequate CCT245737 tumor drug exposure takes a significant antitumor activity.
Shows significant single-agent antitumor activity against a MYC-driven mouse model of B-cell lymphoma and enhances the cytotoxicity of gemcitabine and SN38 in multiple human tumor cell lines and xenograft models. CCT245737 uniquely enhanced gemcitabine antitumor activity to a greater degree than higher doses of either agent alone without increasing toxicity, indicating a true therapeutic advantage for this combination. |
| Enzyme Assay |
Kinase inhibition assays were performed using 33P radiometric methods against a panel of 124 human kinases at 10 µM compound concentration with ATP at Km concentrations. IC50 determinations were conducted using LabChip EZ Reader II or DELFIA assays to confirm selectivity and potency.
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| Cell Assay |
Cellular CHK1 activity was measured using a novel ELISA assay for pS296 CHK1 autophosphorylation, which allowed quantitative measurement of target inhibition in RAS mutant human tumor xenografts at efficacious doses. Cytotoxicity was determined by SRB assay after 96 hours of compound exposure, and cell cycle arrest was measured via pY15 CDK1 inhibition.
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| Animal Protocol |
Dissolved in DPTW (10% DMSO, 20% PEG400, 5% Tween 80 and 65% water) for oral vehicle; 10mg/kg(i.v.); 150mg/kg(p.o.); i.v. or p.o.BALB/c mice
Oral administration in BALB/c mice resulted in complete bioavailability (100%) with extensive tumor exposure. Pharmacokinetic-pharmacodynamic studies demonstrated low predicted human doses and exposures. Genotoxic-induced CHK1 activity and cell cycle arrest were inhibited in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. |
| References |
Oncotarget.2016 Jan 19;7(3):2329-42.
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| Molecular Formula |
C16H16F3N7O
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|---|---|---|
| Molecular Weight |
379.34
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| Exact Mass |
379.137
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| CAS # |
1489389-23-2
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| Related CAS # |
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| PubChem CID |
72202596
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
2.38
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
526
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1(C#N)=NC=C(NC2=NC=C(C(F)(F)F)C(NC[C@H]3OCCNC3)=C2)N=C1
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| InChi Key |
YBYYWUUUGCNAHQ-NSHDSACASA-N
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| InChi Code |
InChI=1S/C16H16F3N7O/c17-16(18,19)12-8-25-14(26-15-9-22-10(4-20)5-24-15)3-13(12)23-7-11-6-21-1-2-27-11/h3,5,8-9,11,21H,1-2,6-7H2,(H2,23,24,25,26)/t11-/m0/s1
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| Chemical Name |
5-[[4-[[(2S)-morpholin-2-yl]methylamino]-5-(trifluoromethyl)pyridin-2-yl]amino]pyrazine-2-carbonitrile
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| Synonyms |
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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 |
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| 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: 75 mg/mL (197.7 mM)
Water: 1 mg/mL (Insoluble) Ethanol: 9 mg/mL (23.7 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 | 2.6362 mL | 13.1808 mL | 26.3616 mL | |
| 5 mM | 0.5272 mL | 2.6362 mL | 5.2723 mL | |
| 10 mM | 0.2636 mL | 1.3181 mL | 2.6362 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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