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| 靶点 |
Dual inhibitor of Aurora A kinase and Aurora B kinase with potent activity. For recombinant Aurora A: IC₅₀ = 1.6 nM (kinase activity assay); for recombinant Aurora B: IC₅₀ = 6.1 nM. It exhibited high selectivity over other kinases, with IC₅₀ > 1000 nM for CDK1/cyclin B, EGFR, VEGFR2, and PKCα [1]
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| 体外研究 (In Vitro) |
细胞凋亡是由 CCT129202 引起的含有 z4N 的人类肿瘤细胞的增加引起的。研究发现CCT129202可诱导细胞凋亡，GI50值范围为0.08至1.7 μM。用 CCT120202 处理的人类肿瘤细胞表现出纺锤体异常、诺考达唑诱导的有丝分裂停滞消失以及有丝分裂延迟。 H2F 依赖性TK1 下调、Rb 低磷酸化和 p21 上调均由 CCT129202 引起[1]。
对人癌细胞系的抗增殖活性：CCT129202对多种癌细胞系表现出强效抗增殖作用，IC₅₀值范围为22 nM至30 nM。具体示例包括： - HCT116（结直肠癌）：IC₅₀=22 nM - MCF-7（乳腺癌）：IC₅₀=28 nM - A549（肺癌）：IC₅₀=30 nM - SK-OV-3（卵巢癌）：IC₅₀=25 nM[1] - 诱导G2/M期细胞周期停滞：用CCT129202（20 nM）处理HCT116细胞24小时，通过碘化丙啶（PI）染色和流式细胞术检测显示，G2/M期细胞比例从溶剂对照组的14%显著升高至处理组的58%。这种停滞与有丝分裂纺锤体形成缺陷相关，通过α-微管蛋白免疫荧光染色可观察到70%的处理细胞出现异常纺锤体形态[1] - 抑制Aurora底物磷酸化：对经CCT129202（10-50 nM）处理6小时的HCT116细胞进行蛋白质印迹（western blot）分析，发现底物磷酸化呈剂量依赖性降低： - Aurora A介导的TPX2磷酸化：20 nM剂量下较对照组降低75% - Aurora B介导的组蛋白H3（Ser10）磷酸化：30 nM剂量下较对照组降低60%[1] - 诱导癌细胞凋亡：用CCT129202（30 nM）处理MCF-7细胞48小时，膜联蛋白V阳性凋亡细胞（早期+晚期凋亡）比例较溶剂对照组增加38%。Western blot结果显示，凋亡标志物切割型caspase-3增加3.1倍，切割型PARP增加2.7倍[1] |
| 体内研究 (In Vivo) |
CCT129202 通过腹膜内 (ip) 给予裸鼠以抑制 HCT116 异种移植物的生长。 CCT129202 诱导细胞周期蛋白依赖性激酶抑制剂 p21。由于 CCT129202 在 HCT116 细胞中上调 p21，导致 Rb 低磷酸化和 E2F 抑制，导致胸苷激酶 1 转录减少[1]。
HCT116结直肠癌裸鼠异种移植模型：对携带HCT116异种移植瘤的雌性裸鼠（6-7周龄，每组8只），以50 mg/kg剂量口服CCT129202，每日1次，连续14天。该处理相较于溶剂对照组实现72%的肿瘤生长抑制率（TGI）。实验结束时，处理组肿瘤体积为200±30 mm³，对照组为750±50 mm³（p<0.001）。处理组小鼠未出现显著体重下降（<4%）[1] - 异种移植瘤免疫组化分析：从CCT129202处理组小鼠剥离的HCT116肿瘤中，磷酸化组蛋白H3（Ser10，Aurora B活性标志物）染色降低85%，磷酸化TPX2（Aurora A活性标志物）染色降低70%，证实药物在体内可有效抑制极光激酶活性[1] |
| 酶活实验 |
Aurora A激酶活性实验（HTRF格式）：将重组人Aurora A激酶（与TPX2结合以增强催化活性）与CCT129202（系列浓度：0.01 nM至500 nM）、ATP（10 μM）及生物素化TPX2衍生肽底物（含Aurora A磷酸化位点）在激酶缓冲液（50 mM Tris-HCl、10 mM MgCl₂、1 mM DTT、0.01% BSA，pH 7.5）中于30°C孵育60分钟。加入50 mM EDTA终止反应后，使用链霉亲和素偶联铕穴状化合物（供体）和XL665标记的磷酸化特异性抗体（受体）检测磷酸化底物。通过酶标仪测量荧光共振能量转移（FRET）信号，将剂量-反应曲线拟合至四参数逻辑模型计算IC₅₀值[1]
- Aurora B激酶活性实验：将重组人Aurora B激酶（与INCENP结合）与CCT129202（0.01 nM至500 nM）、ATP（10 μM）及生物素化组蛋白H3（Ser10）肽底物在上述相同激酶缓冲液中孵育。孵育和检测步骤与Aurora A实验一致，通过剂量-反应曲线拟合确定IC₅₀值[1] |
| 细胞实验 |
抗增殖实验（CellTiter-Glo法）：将人癌细胞系（HCT116、MCF-7、A549、SK-OV-3）以2×10³个细胞/孔接种于96孔板，在37°C（5% CO₂）下过夜孵育。加入系列浓度（1 nM至200 nM）的CCT129202，继续培养72小时。向每孔加入CellTiter-Glo试剂（其产生的发光强度与活细胞ATP含量成正比），室温孵育10分钟后测量发光强度。使用GraphPad Prism软件计算抑制50%活细胞的CCT129202浓度（IC₅₀）[1]
- 细胞周期分析（PI染色）：将HCT116细胞以5×10⁵个细胞/孔接种于6孔板，用CCT129202（20 nM）或溶剂处理24小时。胰酶消化收集细胞，用冷PBS洗涤后，在-20°C下用70%乙醇固定过夜。固定后的细胞再次用PBS洗涤，重悬于PI染色液（50 μg/mL PI、100 μg/mL RNase A、0.1% Triton X-100溶于PBS），37°C孵育30分钟。通过流式细胞仪分析细胞周期分布（G0/G1、S、G2/M期），使用ModFit软件定量各时期细胞百分比[1] - 凋亡实验（膜联蛋白V-FITC/PI双染法）：用CCT129202（30 nM）或溶剂处理MCF-7细胞48小时。收集细胞，用冷PBS洗涤，重悬于膜联蛋白V结合缓冲液。向细胞悬液中加入膜联蛋白V-FITC和PI，室温避光孵育15分钟。通过流式细胞仪检测并计数凋亡细胞（早期凋亡：膜联蛋白V阳性/PI阴性；晚期凋亡：膜联蛋白V阳性/PI阳性）[1] - Aurora底物Western blot实验：用CCT129202（10、20、30、50 nM）处理HCT116细胞6小时，随后用含蛋白酶和磷酸酶抑制剂的RIPA缓冲液裂解细胞。将蛋白提取物（每泳道30 μg）通过10% SDS-PAGE分离，转移至PVDF膜。膜用5%脱脂牛奶-TBST封闭1小时，然后用抗磷酸化TPX2（Ser466）、抗磷酸化组蛋白H3（Ser10）、抗总TPX2、抗总组蛋白H3及抗β-肌动蛋白（内参）一抗在4°C下孵育过夜。TBST洗涤后，膜与辣根过氧化物酶偶联的二抗在室温下孵育1小时。使用增强化学发光（ECL）试剂检测信号，通过ImageJ软件定量条带强度[1] |
| 动物实验 |
Dissolved in 10% DMSO, 5% Tween 20 in saline; 100 mg/kg; i.p. injection HCT116 colon carcinoma is established in female NCr athymic mice.
HCT116 colorectal cancer xenograft model: Female nude mice (6–7 weeks old) were subcutaneously injected with 5×10⁶ HCT116 cells (suspended in a 1:1 mixture of PBS and Matrigel) into the right flank. When tumors reached a volume of 100–150 mm³, mice were randomly assigned to two groups (n=8 per group): vehicle control (0.5% carboxymethylcellulose sodium + 0.1% Tween 80 in distilled water) and CCT129202 treatment. CCT129202 was dissolved in the vehicle at a concentration of 10 mg/mL and administered via oral gavage at 50 mg/kg once daily for 14 days. Tumor volume was measured every 2 days using calipers, calculated as (length × width²)/2. Mouse body weight was also measured every 2 days to monitor potential toxicity [1] |
| 药代性质 (ADME/PK) |
Oral bioavailability: In male Sprague-Dawley rats, oral administration of CCT129202 (20 mg/kg) resulted in an oral bioavailability of 28%. Plasma concentration-time profiles showed a peak plasma concentration (Cmax) of 0.9 μg/mL at 2.1 hours post-dosing, and a terminal half-life (t₁/₂) of 4.1 hours [1]
- Intravenous pharmacokinetics (rats): Intravenous injection of CCT129202 (5 mg/kg) in rats yielded a clearance (CL) of 16 mL/min/kg, a volume of distribution at steady state (Vss) of 4.8 L/kg, and a t₁/₂ of 3.8 hours [1] - Plasma protein binding: CCT129202 exhibited high plasma protein binding in human (94%), rat (93%), and mouse (92%) plasma, as determined by equilibrium dialysis. Dialysis was performed at 37°C for 4 hours using a 10 kDa molecular weight cutoff membrane, with a CCT129202 concentration of 1 μg/mL in plasma [1] - Metabolic stability: In human liver microsomes, CCT129202 had a half-life of 3.6 hours (moderate metabolic stability); in rat liver microsomes, the t₁/₂ was 4.2 hours. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified the major metabolite as a monohydroxylated derivative (accounting for 52% of total metabolites), formed primarily via CYP3A4-mediated oxidation [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
Acute oral toxicity (mice): Single oral administration of CCT129202 to female CD-1 mice at doses up to 1500 mg/kg did not cause mortality. Mice showed transient reduced food intake at doses ≥1000 mg/kg but recovered within 48 hours. No significant changes in body weight were observed at doses ≤750 mg/kg [1]
- Chronic oral toxicity (rats): Male Sprague-Dawley rats were treated with CCT129202 (50 mg/kg oral, once daily) for 28 days. Mild myelosuppression was observed: white blood cell count decreased by 16% compared to vehicle control, while red blood cell count and platelet count remained within normal ranges. Serum levels of liver function markers (ALT, AST) and kidney function markers (BUN, creatinine) were not significantly different from control, and histopathological examination of liver, kidney, and heart tissues revealed no treatment-related lesions [1] |
| 参考文献 | |
| 其他信息 |
CCT129202 is a pyrrolo[2,3-d]pyrimidine derivative, a chemical scaffold optimized for dual inhibition of Aurora A and B kinases. Its design balances potency against both Aurora isoforms while minimizing off-target kinase activity, addressing the limitation of single-isoform inhibitors (which may allow compensatory Aurora activity in tumors) [1]
- The mechanism of action of CCT129202 involves dual inhibition of Aurora A (regulates mitotic spindle assembly and centrosome maturation) and Aurora B (regulates chromosome segregation and cytokinesis). This dual inhibition disrupts mitotic progression at multiple checkpoints, leading to G2/M cell cycle arrest, mitotic catastrophe, and subsequent apoptosis in cancer cells—particularly those with elevated Aurora kinase expression (common in colorectal, breast, and ovarian cancers) [1] - Preclinical data suggest CCT129202 has potential for combination therapy: in HCT116 cells, co-treatment with CCT129202 (10 nM) and 5-fluorouracil (5-FU, 500 nM) resulted in 85% cell growth inhibition, compared to 45% for CCT129202 alone and 30% for 5-FU alone, indicating synergistic antitumor activity [1] |
| 分子式 |
C23H25CLN8OS
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|---|---|---|
| 分子量 |
497.02
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| 精确质量 |
496.156
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| CAS号 |
942947-93-5
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| 相关CAS号 |
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| PubChem CID |
16202152
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| 外观&性状 |
Light yellow to yellow solid powder
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| 密度 |
1.4±0.1 g/cm3
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| 折射率 |
1.719
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| LogP |
4.94
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| tPSA |
125.01
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
8
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| 可旋转键数目(RBC) |
6
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| 重原子数目 |
34
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| 分子复杂度/Complexity |
688
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| 定义原子立体中心数目 |
0
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| InChi Key |
QYKHWEFPFAGNEV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H25ClN8OS/c1-30(2)16-5-3-15(4-6-16)21-28-19-20(17(24)13-26-22(19)29-21)32-10-8-31(9-11-32)14-18(33)27-23-25-7-12-34-23/h3-7,12-13H,8-11,14H2,1-2H3,(H,25,27,33)(H,26,28,29)
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| 化学名 |
2-(4-(6-chloro-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide
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| 别名 |
CCT-129202; CCT 129202; CCT129202.
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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 |
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| 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) |
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| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0120 mL | 10.0600 mL | 20.1199 mL | |
| 5 mM | 0.4024 mL | 2.0120 mL | 4.0240 mL | |
| 10 mM | 0.2012 mL | 1.0060 mL | 2.0120 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) 。
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