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5mg |
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10mg |
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25mg |
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50mg |
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100mg |
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250mg |
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Purity: ≥98%
CCT245737 (CCT-245737) is a novel, potent, orally bioavailable and selective ATP-competitive inhibitor of CHK1 (checkpoint kinase 1) with anticancer activity. It exhibits selectivity over these enzymes that is greater than 5000 times. Without raising toxicity, CCT245737 increased the antitumor activity of gemcitabine to a higher extent than higher doses of either drug alone. An increase in plasma and tumoconcentrations between 3 and 100 mg/kg is seen in CCT2457374. The residual weak in vitro hERG inhibition was lessened by CCT245737's low anticipated doses and exposures in humans.
Targets |
Chk1 (IC50 = 1.3 nM); Chk2 (IC50 = 2440 nM); ERK8 (IC50 = 130 nM); PKD1 (IC50 = 298 nM); RSK2 (IC50 = 361 nM); RSK1 (IC50 = 362 nM); FLT3 (IC50 = 582 nM); MARK3 (IC50 = 698 nM); NUAK1 (IC50 = 711 nM); CLK2 (IC50 = 2440 nM); BRSK1 (IC50 = 1660 nM); AMPK (IC50 = 2970 nM); PHK (IC50 = 3470 nM); CDK2/CyclA (IC50 = 3850 nM); CDK1/CyclB (IC50 = 9030 nM)
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ln Vitro |
CCT245737 (10 µM) demonstrates >80% inhibition of a panel of 124 kinases, with IC50s of 130, 298, 361, and 362 nM for ERK8, PKD1, RSK2, and RSK1 among them[1]. In HT29, SW620, MiaPaCa-2, and Calu6 cell lines, CCT245737 obliterates a G2 checkpoint induced by VP-16; its IC50 values range from 30 to 220 nM[2].
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ln Vivo |
CCT245737 (150 mg/kg p.o.) and LY 188011 (100 mg/kg iv) together suppress tumor growth in HT29 colon cancer xenografts. In SW620 human colon cancer xenografts, CCT245737 (300 mg/kg, p.o.) also prevents the autophosphorylation of pSer296 CHK1 that is induced by LY 188011 (60 mg/kg iv) after 24 hours[1]. In an Eμ-Myc mouse model of human B-cell lymphocytic leukemia, CCT245737 (150 mg/kg, p.o.) by itself dramatically suppresses tumor growth[2].
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Enzyme Assay |
CCT245737 (150 mg/kg p.o.) and LY 188011 (100 mg/kg iv) together suppress tumor growth in HT29 colon cancer xenografts. In SW620 human colon cancer xenografts, CCT245737 (300 mg/kg, p.o.) also prevents the autophosphorylation of pSer296 CHK1 that is induced by LY 188011 (60 mg/kg iv) after 24 hours[1]. In an Eμ-Myc mouse model of human B-cell lymphocytic leukemia, CCT245737 (150 mg/kg, p.o.) by itself dramatically suppresses tumor growth[2].
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Cell Assay |
Cytotoxicity is quantified by utilizing a 96-hour Sulforhodamine B (SRB) assay to find the drug concentration that results in 50% inhibition of tumor cell proliferation (GI50). Using a cell-based ELISA, the inhibition of intracellular CHK1 activity is assessed in order to disrupt a G2 checkpoint induced by VP-16 (mitosis induction assay, MIA). With nocodazole present, the G2 checkpoint abrogation (MIA) IC50 is ascertained using UCN01 as a positive control. The ability of a compound to induce mitosis in relation to its toxicity is measured by the activity index (AI), which is the ratio of MIA IC50 to 96-hour SRB GI50. The combination GI50 of CCT245737 is determined by performing standard potentiation studies with a fixed concentration (GI50) of either SN38 or LY 188011 in combination with a range of CCT245737 concentrations. Potentiation index (PI): the ratio of CCT245737's single GI50 to CCT245737's combination GI50 indicates how well CCT245737 can increase LY 188011 or SN38 cell killing. A PI value greater than one signifies a heightened genotoxic activity. Furthermore, to ascertain the degree to which CCT245737 augments drug cytotoxicity in comparison with the genotoxic agent alone, i.e. conventional PI (ratio GI50 genotoxic alone: GI50 genotoxic combined with non-toxic CCT245737 concentration, Con PI), a series of experiments is conducted using fixed, non- or minimally toxic concentrations of CCT245737 (≤GI20) with a variety of different concentrations of LY 188011 or SN38[2].
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Animal Protocol |
The female NCr athymic mice, aged 6-8 weeks, have s.c. injections of human HT29 colorectal carcinoma cells in their flanks. Dosing started five days after transplantation, or when the tumors reached a mean diameter of 5.5 mm. Compounds 4 (CCT245737) and 41 (150 mg/kg p.o.) are dosed in 10% DMSO 20% PEG 400, 5% Tween 80, and 65% water in the hours following each dose of LY 188011 (100 mg/kg i.v.). Days 0 through 14 are dosed in saline. Three times a week, body weights and tumor measurements are made. Tumors that grow to a predefined humane endpoint (mean diameter <15 mm) are individually culled from the animals[1].
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References |
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Molecular Formula |
C16H16F3N7O
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Molecular Weight |
379.34
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Exact Mass |
379.14
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Elemental Analysis |
C, 50.66; H, 4.25; F, 15.02; N, 25.85; O, 4.22
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CAS # |
1489389-18-5
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Appearance |
White to off-white solid powder
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SMILES |
C1CO[C@H](CN1)CNC2=CC(=NC=C2C(F)(F)F)NC3=NC=C(N=C3)C#N
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InChi Key |
YBYYWUUUGCNAHQ-LLVKDONJSA-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-/m1/s1
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Chemical Name |
5-[[4-[[(2R)-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) |
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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.