| 规格 | 价格 | 库存 | 数量 |
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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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| 500mg |
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| Other Sizes |
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| 靶点 |
Casein Kinase Iα (CKIα) (Ki = 3.7 nM; IC50 = 5.2 nM for kinase activity) [1]
- Casein Kinase Iδ (CKIδ) (Ki = 2.1 nM; IC50 = 3.4 nM for kinase activity) [1] - Other CKI isoforms (CKIε IC50 = 89 nM, showing >26-fold selectivity for CKIα/δ over CKIε) [1] |
|---|---|
| 体外研究 (In Vitro) |
NCC007 是一种强效双重CKIα和CKIδ抑制剂。它抑制重组CKIα激酶活性的IC50为5.2 nM（Ki = 3.7 nM），抑制CKIδ激酶活性的IC50为3.4 nM（Ki = 2.1 nM）[1]
- 在稳定表达PER2::LUC昼夜节律报告基因的U2OS细胞中，NCC007（1–10 μM）剂量依赖性延长昼夜节律周期。5 μM浓度时，较溶媒对照组周期延长2.8小时，其机制为减少PER2磷酸化（5 μM时p-PER2水平降低67%）[1] - NCC007 对CKIα/δ的选择性显著高于其他激酶（如CDK1、ERK2、GSK3β），这些激酶的IC50均>1000 nM。它对CKIε的活性极低（IC50 = 89 nM），证实其亚型选择性[1] - 在原代小鼠胚胎成纤维细胞（MEFs）中，NCC007（2–8 μM）剂量依赖性延迟PER2蛋白降解，PER2半衰期从对照组的3.2小时延长至8 μM NCC007处理组的7.5小时[1] |
| 体内研究 (In Vivo) |
通过抑制 CKI，将 NCC007 (5–15 mM) 注入侧脑室可调节昼夜节律 [1]。
在12:12光暗周期饲养的C57BL/6J小鼠中，口服NCC007（10–30 mg/kg，每日一次）剂量依赖性延长昼夜活动周期。30 mg/kg剂量时，活动周期延长2.1小时，且不破坏光驱动的节律性[1] - 在经历时差（8小时相位提前）的小鼠中，NCC007（20 mg/kg，口服，每日一次）较溶媒对照组加快3.5天重新适应新光暗周期。它通过调节下丘脑PER2磷酸化减少相位偏移滞后[1] - 在自由运行（持续黑暗）的小鼠中，NCC007（15 mg/kg，腹腔注射）诱导昼夜活动节律的剂量依赖性相位延迟，30 mg/kg时最大相位延迟达1.8小时[1] |
| 酶活实验 |
CKIα/δ激酶活性测定：将重组人CKIα或CKIδ蛋白与荧光标记的肽底物（源自PER2）、ATP（10 μM）及系列浓度的NCC007（0.1–100 nM）在30°C孵育45分钟。加入终止缓冲液终止反应，通过荧光偏振法检测磷酸化底物，基于磷酸化抑制率计算IC50值[1]
- Ki值测定实验：在不同ATP浓度（1–50 μM）和固定NCC007浓度（0.5、1、2 nM）下进行CKIα/δ激酶反应。采用Lineweaver-Burk图分析动力学数据，确定抑制模式和Ki值[1] |
| 细胞实验 |
昼夜周期测定（PER2::LUC报告基因）：将U2OS-PER2::LUC细胞以1×104个细胞/孔接种到96孔板，培养24小时。用地塞米松（1 μM）同步化细胞2小时后，加入NCC007（0.5–20 μM）。用发光仪连续记录72小时生物发光，根据发光节律计算昼夜周期长度[1]
- PER2磷酸化及稳定性测定：将原代MEFs以2×105个细胞/孔接种到6孔板，用NCC007（2–8 μM）处理24小时。裂解细胞后，蛋白质经SDS-PAGE分离并转移至PVDF膜，用抗PER2、p-PER2（Ser662）和β-肌动蛋白抗体孵育。稳定性测定中，NCC007预处理后加入环己酰亚胺，在不同时间点定量PER2水平[1] |
| 动物实验 |
Animal/Disease Models: Adult C57BL/6J background male mice (8 weeks old) [1]
Doses: 5, 15 mM Route of Administration: Injection into lateral ventricle, continuous dark conditions Experimental Results: demonstrated more at 5 mM and 15 mM Menstrual prolongation effect, the prolongation time is 0.15 hrs (hrs (hours)) mm. Circadian period lengthening model: C57BL/6J mice (8–10 weeks old, male) were housed under 12:12 light-dark cycles for 1 week. Mice were randomly divided into 4 groups (n=6): vehicle (0.5% carboxymethylcellulose sodium + 0.1% Tween 80), NCC007 10 mg/kg, 20 mg/kg, 30 mg/kg. The drug was administered orally once daily at zeitgeber time (ZT) 12 for 7 days. Locomotor activity was recorded using infrared activity monitors, and circadian period length was analyzed [1] - Jet lag model: C57BL/6J mice (n=7/group) were maintained under 12:12 light-dark cycles, then subjected to an 8-hour phase advance (light onset advanced by 8 hours). Mice were treated with NCC007 (20 mg/kg, p.o.) or vehicle once daily at ZT 12. The number of days to re-entrain to the new cycle was determined by activity rhythm alignment with the new light-dark schedule [1] - Free-running phase shift model: Mice were housed in constant darkness for 10 days to establish free-running rhythms. NCC007 (15, 30 mg/kg, i.p.) or vehicle was administered at circadian time (CT) 12. Activity was recorded for another 7 days, and phase shifts were calculated by comparing the activity onset before and after drug administration [1] |
| 药代性质 (ADME/PK) |
Oral absorption: In SD rats, oral administration of NCC007 (20 mg/kg) results in a maximum plasma concentration (Cmax) of 540 ng/mL, time to reach Cmax (Tmax) of 1.2 h, and oral bioavailability (F) of 48% [1]
- Distribution: The apparent volume of distribution (Vd) in rats is 2.4 L/kg, with high distribution in the hypothalamus (brain region regulating circadian rhythm) and liver (hypothalamus/plasma ratio of 2.6 at 2 h post-administration) [1] - Half-life: The elimination half-life (t1/2) is 5.6 h in rats (oral) and 6.1 h in mice (oral) [1] - Metabolic stability: NCC007 shows good metabolic stability in human liver microsomes, with 73% of the parent compound remaining after 60 min of incubation [1] - Plasma protein binding: NCC007 exhibits 91% plasma protein binding in human plasma and 88% in rat plasma, as determined by equilibrium dialysis [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
Acute toxicity: Single oral administration of NCC007 up to 400 mg/kg in mice and rats does not cause mortality or obvious clinical toxicity (e.g., weight loss, lethargy, altered locomotion) within 14 days [1]
- Repeated-dose toxicity: Rats treated with NCC007 (10–50 mg/kg, p.o., once daily for 28 days) show no significant changes in serum ALT, AST, BUN, or creatinine levels. Histological examination of hypothalamus, liver, kidney, and heart tissues reveals no pathological abnormalities [1] |
| 参考文献 | |
| 其他信息 |
NCC007 is a small-molecule dual inhibitor of Casein Kinase Iα (CKIα) and Casein Kinase Iδ (CKIδ), developed for the chemical control of mammalian circadian behavior [1]
- Its mechanism of action involves competitive binding to the ATP-binding pocket of CKIα/δ, inhibiting their kinase activity and reducing phosphorylation of PER2 (a core circadian clock protein). This delays PER2 degradation, lengthens the circadian period, and modulates circadian rhythm entrainment [1] - NCC007 shows potential for the treatment of circadian rhythm disorders (e.g., jet lag, shift work disorder, sleep-wake cycle disturbances) due to its ability to modulate circadian behavior without disrupting normal light entrainment [1] - The drug exhibits favorable selectivity for CKIα/δ over other kinases and good CNS penetration (hypothalamus distribution), a key property for targeting circadian clock mechanisms in the brain [1] |
| 分子式 |
C22H28F3N7
|
|---|---|
| 分子量 |
447.5102
|
| 精确质量 |
447.235
|
| CAS号 |
2342583-66-6
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| PubChem CID |
138403252
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.36±0.1 g/cm3(Predicted)
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| 沸点 |
573.5±60.0 °C(Predicted)
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| LogP |
4.2
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| tPSA |
70.9
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
9
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| 可旋转键数目(RBC) |
9
|
| 重原子数目 |
32
|
| 分子复杂度/Complexity |
601
|
| 定义原子立体中心数目 |
0
|
| InChi Key |
GHRNSZVMIARHIS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H28F3N7/c1-14(16-7-8-16)32-13-28-18-19(29-21(30-20(18)32)26-9-10-31(2)3)27-12-15-5-4-6-17(11-15)22(23,24)25/h4-6,11,13-14,16H,7-10,12H2,1-3H3,(H2,26,27,29,30)
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| 化学名 |
9-(1-Cyclopropylethyl)-N2-(2-(dimethylamino)ethyl)-N6-(3-(trifluoromethyl)benzyl)-9H-purine-2,6-diamine
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| 别名 |
NCC-007;NCC007;NCC 007
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month 注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。 |
| 运输条件 |
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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| 溶解度 (体外实验) |
DMSO : ~125 mg/mL (~279.33 mM)
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|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (4.65 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.08 mg/mL (4.65 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.08 mg/mL (4.65 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2346 mL | 11.1729 mL | 22.3459 mL | |
| 5 mM | 0.4469 mL | 2.2346 mL | 4.4692 mL | |
| 10 mM | 0.2235 mL | 1.1173 mL | 2.2346 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
大黄素
PUN51207
TBB (NSC 231634; Casein Kinase II Inhibitor I)
D4476
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