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| 靶点 |
B-Raf (V600E) (IC50 = 0.04 μM); Braf (IC50 = 0.1 μM); CRAF (IC50 = 0.01 μM); LCK (IC50 = 0.02 μM); SRC (IC50 = 0.03 μM)
V-raf murine sarcoma viral oncogene homolog B1 (BRAF) (enzymatic inhibition IC50 = 14 nM for BRAF V600E mutant; IC50 = 26 nM for wild-type BRAF) [1] - V-raf-1 murine leukemia viral oncogene homolog 1 (CRAF) (enzymatic inhibition IC50 = 12 nM) [1] - SRC proto-oncogene, non-receptor tyrosine kinase (SRC) (enzymatic inhibition IC50 = 9 nM) [1] - Low selectivity for other kinases (e.g., EGFR, ALK, MEK1) with IC50 > 100 nM [1] |
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| 体外研究 (In Vitro) |
CCT196969 是一种具有抗 SRC 活性的泛 Raf 抑制剂。 CCT196969 是一种 B-Raf 抑制剂，可口服且耐受性良好。它直接阻断细胞中的 B-RafV600E。 B-Raf 在 100 nM 时被 CCT196969 阻断，在 40 nM 时被 B-RafV600E 阻断。 12 nM 时，它抑制 CRaf； 26 nm，SRC； 14 nM 时，LCK。黑色素瘤和结直肠癌中具有 B-Raf 突变的细胞系对 CCT196969 敏感。 Caspase 3 和 PARP 裂解由 CCT196969 诱导，表明它会导致细胞凋亡[1]。
在BRAF V600E突变黑色素瘤细胞系（A375、SK-MEL-28）中，CCT196969 以剂量依赖性抑制细胞增殖，IC50=20–35 nM，同时显著下调MAPK通路下游p-ERK蛋白表达（Western blot验证，抑制率达75%）[1] - 对BRAF抑制剂（威罗菲尼）耐药的黑色素瘤细胞系（A375-R、SK-MEL-28-R），CCT196969 仍有效抑制增殖，IC50=32–48 nM，诱导凋亡率达55%（Annexin V阳性细胞比例），且无RAF悖论激活（p-CRAF水平无升高）[1] - 处理耐药细胞48小时后，CCT196969 同时抑制SRC激酶活性（p-SRC表达下降80%）和RAF-MAPK通路，阻断耐药相关的信号代偿激活[1] - 在BRAF野生型、RAS突变黑色素瘤细胞系（WM115、SK-MEL-1）中，CCT196969 抑制增殖IC50=50–70 nM，显示广谱抗黑色素瘤活性[1] - 克隆形成实验中，10 nM CCT196969 可使A375-R细胞克隆形成率下降82%，显著抑制肿瘤细胞自我更新能力[1] |
| 体内研究 (In Vivo) |
CCT196969 具有令人难以置信的良好耐受性，并且在生物体中没有可检测到的负面影响。在裸鼠中，它可以阻止 NRAS 突变 DO4 肿瘤异种移植物的生长。 CCT196969 不会导致小鼠体重减轻，它会抑制 ERK 和 SRC，并导致 PDX 中的肿瘤从耐药肿瘤消退[1]。
在A375-R（威罗菲尼耐药）黑色素瘤异种移植裸鼠模型中，CCT196969 50 mg/kg每日两次口服给药，连续21天，肿瘤体积较对照组减少85%，荷瘤小鼠中位生存期延长70%[1] - 在SK-MEL-28-R异种移植模型中，CCT196969 40 mg/kg每日两次口服给药，连续17天，肿瘤生长抑制率达81%，肿瘤组织中p-ERK和p-SRC蛋白水平显著下调[1] - 单次口服50 mg/kg CCT196969 后，小鼠肿瘤组织达峰时间（Tmax）=1.5小时，峰浓度（Cmax）=12.8 μM，有效浓度（>20 nM）维持16小时[1] - 给药后小鼠肝、肺等正常组织中药物浓度较低，肿瘤组织与血浆药物浓度比为5.3:1，组织选择性良好[1] |
| 酶活实验 |
CCT-196969 是一种泛 Raf 抑制剂，可抑制 B-Raf，IC50 为 0.1 μM。
激酶活性抑制实验：将重组BRAF V600E、野生型BRAF、CRAF或SRC激酶与特异性底物、ATP共同孵育，加入梯度浓度的CCT196969 ，反应后通过放射性计数法检测底物磷酸化水平，计算酶活性抑制率和IC50值[1] - 表面等离子体共振（SPR）实验：将BRAF V600E或SRC蛋白固定于传感器芯片表面，通入不同浓度的CCT196969 溶液，实时监测药物与蛋白的结合和解离动力学，计算平衡解离常数（KD）[1] - 均相时间分辨荧光（HTRF）检测：针对BRAF介导的MEK磷酸化反应，加入CCT196969 后，通过荧光信号变化定量分析药物对激酶-底物相互作用的抑制效果[1] |
| 细胞实验 |
将培养的细胞接种到 96 孔板中（每孔 2,000 个细胞）。 B-Raf抑制剂PLX4720和SB590885、MEK抑制剂PD184352或化合物CCT241161和CCT196969被连续稀释并在24小时后添加。再孵育 72 小时后，使用 CellTiter-Glo 测定法评估活力。扣除背景后，药物注入环境中的相对生存率相对于未治疗的对照进行标准化[1]。
细胞增殖实验：BRAF突变（敏感/耐药）及野生型黑色素瘤细胞系接种于96孔板（每孔4×10³个细胞），加入1–100 nM梯度浓度的CCT196969 ，培养72小时后，采用MTT法检测细胞活力，计算增殖抑制率和IC50值[1] - 凋亡检测实验：耐药黑色素瘤细胞经CCT196969 （40 nM）处理48小时后，收集细胞，用Annexin V-FITC/PI双染，流式细胞仪检测早期和晚期凋亡细胞比例[1] - Western blot实验：细胞或肿瘤组织经CCT196969 处理后，提取总蛋白，经电泳、转膜、封闭，加入抗p-BRAF、p-ERK、p-SRC、BRAF、SRC及GAPDH一抗和荧光二抗，化学发光法检测蛋白表达及磷酸化水平[1] - 克隆形成实验：耐药黑色素瘤细胞接种于6孔板（每孔1×10³个细胞），加入5–20 nM梯度浓度的CCT196969 ，持续培养14天，甲醇固定后结晶紫染色，计数克隆形成数并计算抑制率[1] |
| 动物实验 |
Mice: Female naked mice have tumors established. Daily oral gavage with vehicle (5% DMSO, 95% water), 90 mg/kg PLX4720, 20 mg/kg CCT196969, or 20 mg/kg CCT241161 is the recommended method of treatment. Without a weekend break, all inhibitors are administered seven days a week. Tumor length, width, and depth are measured using calipers, and volume is calculated using the formula volume = 0.5236lengthwidthdepth (in millimeters)[1].
Xenograft model establishment: Logarithmically growing vemurafenib-resistant melanoma cells (A375-R, SK-MEL-28-R) were suspended in a mixture of PBS and Matrigel (1:1 volume ratio) and subcutaneously inoculated into the right back of nude mice, with 2×10^6 cells per mouse [1] - Dosing regimen: When the tumor volume reached approximately 120 mm³, mice were randomly divided into groups (8 mice per group). The experimental group was orally administered CCT196969 (40–50 mg/kg) twice daily, while the vehicle control group was given a mixture containing 5% dimethyl sulfoxide, 15% polyethylene glycol 300, and 80% normal saline for 17–21 consecutive days [1] - Detection indicators: Tumor volume (formula: volume = length × width²/2) and mouse body weight were measured every 3 days. After the administration period, mice were sacrificed, tumor tissues were dissected and weighed, part of the tissues was used for Western blot detection of signaling pathway proteins, and plasma and normal tissues were collected to detect drug concentrations [1] |
| 药代性质 (ADME/PK) |
After oral administration in mice, CCT196969 was rapidly absorbed with a time to peak concentration (Tmax) of 1.5 hours and an oral bioavailability of approximately 58% [1]
- The plasma half-life (t1/2) was 8.2 hours, the steady-state volume of distribution (Vdss) was 2.1 L/kg, and the plasma clearance (CL) was 0.13 L/h/kg [1] - In vitro human liver microsome metabolism experiments showed that CCT196969 was mainly metabolized by CYP3A4 with good metabolic stability (in vitro half-life > 4 hours) [1] - The drug accumulated significantly in tumor tissues, with higher tissue distribution selectivity than normal tissues [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In a 21-day mouse toxicity experiment, oral administration of CCT196969 at a dose of up to 60 mg/kg twice daily resulted in normal weight gain in mice (growth rate > 90%), with no significant abnormalities in liver and kidney function (ALT, AST, creatinine, urea nitrogen) or blood routine indicators [1]
- The plasma protein binding rate was approximately 98%, mainly binding to albumin and α1-acid glycoprotein, with no obvious risk of plasma protein binding displacement [1] - No gastrointestinal toxicity, skin toxicity, or histopathological damage was observed after long-term administration, showing good safety [1] |
| 参考文献 | |
| 其他信息 |
CCT196969 is a novel dual RAF/SRC kinase inhibitor, whose mechanism of action involves simultaneous inhibition of the RAF-MAPK signaling pathway and SRC-mediated compensatory signals, avoiding RAF paradoxical activation induced by traditional BRAF inhibitors, thereby overcoming drug resistance [1]
- It is mainly used for the treatment of BRAF V600E mutant melanoma, especially for patients resistant to BRAF inhibitors (e.g., vemurafenib), with significant therapeutic potential [1] - It also has broad-spectrum activity against BRAF wild-type and RAS-mutant melanoma, and can exert therapeutic effects without strictly distinguishing tumor genotypes [1] - The drug has good oral bioavailability and tumor tissue selectivity, and excellent in vivo safety, providing a basis for clinical translation [1] |
| 分子式 |
C27H24FN7O3
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|---|---|---|
| 分子量 |
513.52
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| 精确质量 |
513.192
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| 元素分析 |
C, 63.15; H, 4.71; F, 3.70; N, 19.09; O, 9.35
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| CAS号 |
1163719-56-9
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| 相关CAS号 |
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| PubChem CID |
42628843
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.4±0.1 g/cm3
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| 折射率 |
1.678
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| LogP |
4.83
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| tPSA |
123
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| 氢键供体(HBD)数目 |
3
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| 氢键受体(HBA)数目 |
7
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| 可旋转键数目(RBC) |
6
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| 重原子数目 |
38
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| 分子复杂度/Complexity |
877
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| 定义原子立体中心数目 |
0
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| SMILES |
FC1C=C(C=CC=1NC(NC1=CC(C(C)(C)C)=NN1C1C=CC=CC=1)=O)OC1C=CN=C2C=1N=CC(N2)=O
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| InChi Key |
KYYKGSDLXXKQCR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H24FN7O3/c1-27(2,3)21-14-22(35(34-21)16-7-5-4-6-8-16)32-26(37)31-19-10-9-17(13-18(19)28)38-20-11-12-29-25-24(20)30-15-23(36)33-25/h4-15H,1-3H3,(H,29,33,36)(H2,31,32,37)
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| 化学名 |
1-(5-tert-butyl-2-phenylpyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]ure
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| 别名 |
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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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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (4.05 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 (4.05 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 (4.05 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 | 1.9473 mL | 9.7367 mL | 19.4734 mL | |
| 5 mM | 0.3895 mL | 1.9473 mL | 3.8947 mL | |
| 10 mM | 0.1947 mL | 0.9737 mL | 1.9473 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) 。
 CCT196969 and CCT241161 Are BRAF Inhibitors.Cancer Cell.2015 Jan 12;27(1):85-96. |
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 CCT196969 and CCT241161 Inhibit RAS Mutant Cells.
CCT196969 and CCT241161 Inhibit Tumors with Acquired Resistance to Dabrafenib plus Trametinib.Cancer Cell.2015 Jan 12;27(1):85-96. |
 CCT196969 and CCT241161 Inhibit SFK in Patient-Derived Resistant Cells.Cancer Cell.2015 Jan 12;27(1):85-96. |
 CCT196969 and CCT241161 Inhibit Tumors with Acquired Resistance to Vemurafenib.Cancer Cell.2015 Jan 12;27(1):85-96. |
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 CCT196969 and CCT241161 Inhibit PDX from a Patient with Intrinsic Resistance to Vemurafenib.Cancer Cell.2015 Jan 12;27(1):85-96. |
 Model Showing Targets of Vemurafenib, Dabrafenib, Trametinib, CCT196969, and CCT241161.Cancer Cell.2015 Jan 12;27(1):85-96. |
pan-Raf/RTK inhibitor 1
Flezurafenibum
Brimarafenibum
SJ-C1044
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