CCT244747

上海金畔生物科技有限公司为生命科学和医药研发人员提供生物活性分子抑制剂、激动剂、特异性抑制剂、化合物库、重组蛋白,专注于信号通路和疾病研究领域。

CCT244747  纯度: ≥99.0%

CCT244747 是一种有效的,可口服的,高度选择性的 CHK1 抑制剂,IC50 值为 7.7 nM;CCT244747 可废除 G2 检查点,IC50 值为 29 nM。

CCT244747

CCT244747 Chemical Structure

CAS No. : 1404095-34-6

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10 mM * 1 mL in DMSO ¥1348 In-stock
2 mg ¥900 In-stock
5 mg ¥1500 In-stock
10 mg ¥2500 In-stock
25 mg ¥4500 In-stock
50 mg ¥7500 In-stock
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CCT244747 相关产品

相关化合物库:

  • Bioactive Compound Library Plus
  • Cell Cycle/DNA Damage Compound Library
  • Kinase Inhibitor Library
  • Anti-Cancer Compound Library
  • Anti-Aging Compound Library
  • Orally Active Compound Library
  • Chemical Probe Library
  • Anti-Lung Cancer Compound Library

生物活性

CCT244747 is a potent, orally bioavailable and highly selective CHK1 inhibitor, with an IC50 of 7.7 nM; CCT244747 also abrogates G2 checkpoint with an IC50 of 29 nM.

IC50 & Target[1]

Chk1

7.7 nM (IC50)

体外研究
(In Vitro)

CCT244747 poorly inhibits CHK2 (IC50 >10 μM) and CDK1 (IC50 >10 μM). CCT244747 has potent activities against CHK1, RSK1, RSK2, AMPK, BRSK1, IRAK1,and TrkA, with >80% inhibition. CCT244747 (10 μM) exhibits <25% inhibition of the other ion channels including hNav1.5, hKv4.3/hKChIP2, hCav1.2, hKv1.5, hKCNQ1/hminK, hHCN4[1]. CCT244747 inhibits FLT3 with an IC50 of 600 nM. CCT244747 (0.5 μM) overcomes genotoxic-induced S and G2 cell cycle arrest in human colon cancer cell lines. CCT244747 inhibits cellular CHK1 function with IC50s ranging from 29 nM to 170 nM for cellular G2 checkpoint abrogation (MIA, mitosis induction assay) in HT29, SW620, MiaPaCa-2, and Calu6 cell lines; the GI50s are between 0.33 and 3μM. CCT244747 (0.3 μM) inhibits SN38 and gemcitabine-induced CHK1 activity in HT29 and SW620 colon cancer cell lines and this correlates with abrogation of cell cycle arrest, induction of DNA damage and apoptosis[2]. CCT244747 (0.5-2.0 μM) increases the sensitivity of bladder and head and neck cancer cell lines (T24, RT112 and Cal27) to radiation[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

体内研究
(In Vivo)

CCT244747 (100 mg/kg po, qd7d) significantly reduces tumor burden in human tumor xenografts. CCT244747 (100-300 mg/kg, po) inhibits gemcitabine-induced pS296 CHK1 for up to 24 h in HT29 colon tumor xenografts[1]. CCT244747 (75 mg/kg, p.o.) in combination with gemcitabine has potent antitumor effects in HT29 colon tumor xenografts and Calu6 human lung cancer xenografts. CCT244747 (150 mg/kg p.o.) also shows antitumor activities with irinotecan in SW620 human colon tumor xenografts[2]. CCT244747 (100 mg/kg, p.o.) exhibits radiosensitization activity in Cal27 xenografts[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

分子量

408.46

Formula

C20H24N8O2

CAS 号

1404095-34-6

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
溶解性数据
In Vitro: 

DMSO : 50 mg/mL (122.41 mM; Need ultrasonic)

配制储备液
浓度 溶剂体积 质量 1 mg 5 mg 10 mg
1 mM 2.4482 mL 12.2411 mL 24.4822 mL
5 mM 0.4896 mL 2.4482 mL 4.8964 mL
10 mM 0.2448 mL 1.2241 mL 2.4482 mL

*

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效
储备液的保存方式和期限:-80°C, 6 months; -20°C, 1 month。-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。

In Vivo:

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液,再依次添加助溶剂:

——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用; 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶

  • 1.

    请依序添加每种溶剂: 10% DMSO    40% PEG300    5% Tween-80    45% saline

    Solubility: ≥ 2.5 mg/mL (6.12 mM); Clear solution

    此方案可获得 ≥ 2.5 mg/mL (6.12 mM,饱和度未知) 的澄清溶液。

    以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。

    将 0.9 g 氯化钠,完全溶解于 100 mL ddH₂O 中,得到澄清透明的生理盐水溶液

*以上所有助溶剂都可在 上海金畔生物科技有限公司 网站选购。
参考文献
  • [1]. Lainchbury M, et al. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem. 2012 Nov 26;55(22):10229-40.

    [2]. Walton MI, et al. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012 Oct 15;18(20):5650-61.

    [3]. Patel R, et al. An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation. Radiother Oncol. 2017 Mar;122(3):470-475.

Kinase Assay
[1]

CHK1 kinase activity is measured in a microfluidic assay that monitored the separation of a phosphorylated product from its substrate. The assay is run on an EZ Reader II using separation buffer containing CR-8 (500 nM). An ECHO® 550 acoustic dispenser is used to generate duplicate 8 pt dilution curves directly into 384 polypropylene assay plates. For each compound a 50 μM stock concentration in 100% DMSO is used. The total amount of DMSO dispensed per well is 250 nL to give a final assay concentration of 2.5% DMSO and compound concentrations in the range 0.5-1000 nM. To this assay plate, 6 PL CHK1 (2 nM final concentration, in-house protein preparation), 2 PL peptide 10 (5-FAM-KKKVSRSGLYRSPSMPENLNRPR-COOH, 1.5 PM final concentration) and 2 PL ATP (90 PM final concentration) all diluted in kinase buffer (HEPES 50 mM, NaN3 0.02%, BSA 0.01%, sodium orthovanadate 0.1 mM, DTT 1 mM, MgCl2 2 mM, Tween20 0.1%) are added. The plate is sealed and centrifuged (1 min, 1000 rpm) before ncubation for 1 h at room temperature. The reaction is stopped by the addition of separation buffer (90 PL). The plate is read on an EZ Reader II, using a 12-sipper chip with instrument settings of -1.5 psi and 1750 ΔV. The percentage conversion of product from substrate is generated automatically and the percentage inhibition is calculated relative to blank wells (containing no enzyme and 2.5% DMSO) and total wells (containing all reagents and 2.5% DMSO). IC50 values are calculated in GraphPad Prism5 using a non linear regression fit of the log (inhibitor) vs response with variable slope equation[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Compound cytotoxicity and the ability of CHK1 inhibitors to enhance SN38 (the active metabolite of the topoisomerase I inhibitor irinotecan) and gemcitabine (an antimetabolite) cytotoxicity is assessed using a 96 h sulforhodamine B assay (SRB). HT29 or SW620 cells are seeded at 1.6 to 3.2 × 103 cells per well in 96-well plates in a volume of 160 μL medium and allowed to attach for 36 h prior to treatment. For cytotoxicity assays, CHK1 inhibitors (10 mM stock in DMSO) are serially diluted in medium from a starting concentration of 250 PM and then 40 PL is added to appropriate wells in quadruplicate to give a final concentration range of 50-0.1 PM (10 concentrations). Genotoxic agents (SN38; 10 mM stock in DMSO) are serially diluted in medium from a starting concentration of 2 PM and 40 PL is added to each well inquadruplicate to give final concentrations from 200-0.39 nM (10 concentrations). Cells are incubated for 96 h (four doublings) at 37°C in a humidified 5% CO2 environment and then fixed and stained with SRB. Appropriate controls are included and results are expressed as the concentration of test compound required to inhibit cell growth by 50% relative to untreated controls (SRB IC50). Potentiation assays involved adding a fixed SRB IC50 concentration of either gemcitabine or SN38 in a volume of 20 μL of medium (10× final concentration), to each well in quadruplicate and mixing for 1 min. CHK1 inhibitor (10 mM stock) is serially diluted from a starting concentration of 50 PM in medium and 20 PL is added per well in quadruplicate to give a final concentration range of 5-0.039 PM (8 concentrations). After mixing for 1 min the cells are incubated at 37°C in a humidified atmosphere for 96 h (four doublings) prior to fixing and SRB staining. Untreated and genotoxic alone treated controls are included and results are expressed as the concentration of CHK1 inhibitor required to inhibit cell growth by 50% (potentiation IC50). The potentiation index (PI) is used as a measure of the ability of the CHK1 inhibitor to enhance SN38 or gemcitabine cytotoxicity and is the ratio of the SRB IC50 versus potentiation IC50 (PI = SRB IC50 / Potentiation IC50)[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Female BALB/c mice (6 weeks old) are kept in a controlled environment with food and sterilized water available ad libitum. Animals weighed 20 (±2) g at the time of experiment. Dosing solutions are prepared by dissolving the compounds in 10% DMSO and 5% Tween20 in 85% saline. The compounds are administered i.v. and p.o., individually. Animals are warmed before receiving a single i.v. bolus injection into a lateral tail vein. Oral administration is by oral gavage. Blood is collected at selected time points (1 h and 6 h after dosing) by cardiac puncture under anesthesia into heparinized syringes, transferred to micro centrifuge tubes, and centrifuged at 4500 × g for 2 min to obtain plasma. Quantitative analysis is performed by high performance liquid chromatography tandem mass spectrometry on a triple quadrupole instrument using multiple reaction monitoring of selected transitions with olomoucine used as internal standard. Quantitation is performed against a standard curve ranging from concentrations of 2-1000 nM in the matrix measured. Quality controls are included at the level of 25, 250 and 750 nM. If required, samples are diluted in the matrix of interest[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

参考文献
  • [1]. Lainchbury M, et al. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem. 2012 Nov 26;55(22):10229-40.

    [2]. Walton MI, et al. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012 Oct 15;18(20):5650-61.

    [3]. Patel R, et al. An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation. Radiother Oncol. 2017 Mar;122(3):470-475.

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