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| 靶点 |
Reversible farnesyl growth enzyme kinase with a slow on/off rate is CP-609754 (CP-609,754). The analysis of compounds tagged with [35S]methionine using SDS-PAGE [1] indicates that CP-609754 is competitive for the isoprene receptor (H-Ras protein), but not for the isoprene donor farnesyl PPI. When it comes to binding to Ras protein, CP-609754 reacts to and competes with the farnesyltransferase-farnesylPPI complex. In 3T3 transfectants, CP-609754 specifically prevents the farnesylation of H- and K-Ras proteins [1].
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| 体外研究 (In Vitro) |
具有缓慢开/关速率的可逆法呢基生长酶激酶是 CP-609754 (CP-609,754)。使用 SDS-PAGE 对 [35S] 蛋氨酸标记的化合物进行分析 [1] 表明 CP-609754 与异戊二烯受体（H-Ras 蛋白）具有竞争性，但与异戊二烯供体法尼基 PPI 不具有竞争性。当与 Ras 蛋白结合时，CP-609754 会与法尼基转移酶-法尼基 PPI 复合物发生反应并竞争。在 3T3 转染子中，CP-609754 特异性阻止 H- 和 K-Ras 蛋白的法呢基化 [1]。
在转染了突变H-ras (61L)的3T3细胞系中，通过SDS-PAGE分析[³⁵S]甲硫氨酸标记的物质，测得CP-609,754抑制突变H-Ras法尼基化的IC50为1.72 ng/mL。 在浓度高达4790 ng/mL时，在K-Ras转染的细胞系中未观察到这种抑制效应，可能是因为在法尼基转移酶抑制剂存在下，K-Ras可以被香叶基香叶基转移酶-I替代性异戊二烯化。 使用氚标记的异戊二烯前体进行的分析证实，CP-609,754能选择性抑制3T3转染细胞中H-Ras和K-Ras蛋白的法尼基化。 |
| 体内研究 (In Vivo) |
据报道，CP-609754 (CP-609,754) 具有抗 3T3 H-ras (61L) 癌症的体内活性 [1]。通过持续腹腔输注CP-609754实现肿瘤抑制；肿瘤生长抑制>50%，肿瘤法尼基转录酶活性抑制>30%，CP-609754肿瘤生长浓度保持在118 ng/mL以上。当 CP-609754 每天两次应用于侧壁时，肿瘤消退达到 100 mg/kg 的剂量 [1]。
在携带3T3 H-ras (61L)肿瘤的小鼠中，口服给予CP-609,754 100 mg/kg，每日两次，可导致肿瘤消退。抑制肿瘤生长的ED₅₀为28 mg/kg。 当血浆浓度维持在118 ng/mL以上时，持续腹腔输注CP-609,754可抑制小鼠肿瘤生长超过50%，并抑制肿瘤法尼基转移酶活性超过30%。 |
| 酶活实验 |
使用H-Ras和K-Ras蛋白作为底物，通过测量法尼基团的转移来测定CP-609,754对重组人法尼基转移酶的抑制活性，并由此计算IC50值。
还评估了该药物对使用H-Ras和K-Ras蛋白CAAX突变体的重组人香叶基香叶基转移酶I活性的抑制。 动力学研究表明，CP-609,754是一种可逆性抑制剂，对Ras蛋白受体具有竞争性，对法尼基焦磷酸供体具有非竞争性，表明其与法尼基转移酶-法尼基焦磷酸复合物相互作用。 |
| 细胞实验 |
使用转染了突变H-ras (61L)的3T3细胞评估了CP-609,754在完整细胞中对法尼基化的抑制。细胞用药物处理后，用[³⁵S]甲硫氨酸进行代谢标记，然后裂解。通过SDS-PAGE分离蛋白，并分析Ras的法尼基化状态。
另一种检测方法使用氚标记的异戊二烯前体代替[³⁵S]甲硫氨酸，以特异性追踪转染细胞中蛋白的异戊二烯化。 |
| 动物实验 |
For in vivo antitumor activity, mice bearing 3T3 H-ras (61L) tumors were treated with CP-609,754 administered orally at 100 mg/kg twice daily. Tumor volume was monitored to assess regression and calculate the ED₅₀ for growth inhibition.
For pharmacodynamic analysis, mice received continuous intraperitoneal infusion of CP-609,754 to maintain steady plasma concentrations. Tumor growth and tumor farnesyltransferase activity were measured. |
| 药代性质 (ADME/PK) |
In a phase I clinical trial, CP-609,754 was administered orally as tablets to patients with advanced solid tumors. Pharmacokinetic parameters were derived from plasma concentration-time data.
The half-life (T₁/₂) was approximately 3 hours. At the 640 mg twice daily dose, the mean maximum plasma concentration (Cmax) was 1250 ng/mL (day 1 morning dose) and 1110 ng/mL (day 15 morning dose). The time to maximum concentration (Tmax) was 1-2 hours after the morning dose. The mean area under the curve over the dosing interval (AUC₀-τ) on day 15 was 3650 hng/mL for the morning dose and 3480 hng/mL for the evening dose. The observed end-of-dosing-interval plasma concentration (Cmin) on day 15 was 46 ng/mL (morning) and 101 ng/mL (evening). Accumulation with multiple dosing was less than expected, with mean accumulation ratios of 0.75 (morning) and 0.54 (evening). Exposure increased proportionally with dose, and oral absorption was rapid. |
| 毒性/毒理 (Toxicokinetics/TK) |
In the phase I trial, the dose-limiting toxicity (DLT) was grade 3 neuropathy (dizziness and unsteady gait), observed in 1 of 6 patients at the 640 mg twice daily dose level.
Other treatment-related grade 3/4 adverse events included: lymphopenia (common across doses), anemia, leukopenia (including one case of febrile neutropenia at 640 mg BID), thrombocytopenia, hypokalemia, asthenia, pain, and confusion. One patient on warfarin developed coagulopathy with increased prothrombin time, suggesting a potential drug interaction. Grade 3 elevations in gamma glutamyltransferase and serum creatinine were observed in some patients, though the latter was attributed to disease progression in one case. No treatment-related deaths occurred. Common adverse events at 640 mg BID included neuropathy, asthenia, pain, diarrhea, nausea, and vomiting (mostly grades 1-2). |
| 参考文献 | |
| 其他信息 |
LNK 754 has been investigated in Mild Alzheimer's Disease.
CP-609,754 is a quinolinone derivative that inhibits farnesyl protein transferase, an enzyme that mediates the farnesylation of RAS, causing possible inhibition of the RAS pathway. CP-609,754 is also known as OSI-754 or LNK-754. Its chemical name is 6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethynylphenyl)-1-methyl-2(1H)-quinolinone, (2R,3R)-2,3-dihydroxybutanedioic (1:1), a D(-) tartrate salt. It is a reversible inhibitor of farnesyltransferase with a slow on/off rate. The primary mechanism is inhibition of Ras protein farnesylation, a critical step for its membrane localization and oncogenic signaling. Inhibition of other farnesylated proteins (e.g., RhoB) may also contribute to its effects. Based on preclinical data, maintaining plasma concentrations above 118 ng/mL was projected to be necessary for clinical efficacy against Ras-expressing tumors. In the phase I study, the recommended phase II dose (RP2D) was determined to be ≥640 mg administered orally twice daily. Although no objective tumor responses were observed, 10 patients had prolonged disease stabilization (>2 months, up to 367 days) across various tumor types (e.g., colorectal, renal cell, bronchoalveolar carcinoma). |
| 分子式 |
C29H22CLN3O2
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| 分子量 |
479.96
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| 精确质量 |
479.14
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| CAS号 |
1190094-64-4
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| 相关CAS号 |
(Rac)-CP-609754;439153-64-7
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| PubChem CID |
46208720
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| 外观&性状 |
Off-white to yellow solid powder
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| 密度 |
1.23±0.1 g/cm3
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| 沸点 |
702.4±60.0 °C
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| LogP |
4.857
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| tPSA |
60.05
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
3
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| 可旋转键数目(RBC) |
5
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| 重原子数目 |
35
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| 分子复杂度/Complexity |
874
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| 定义原子立体中心数目 |
1
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| SMILES |
CN1C=NC=C1[C@@](C2=CC=C(C=C2)Cl)(C3=CC4=C(C=C3)N(C(=O)C=C4C5=CC=CC(=C5)C#C)C)O
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| InChi Key |
JAHDAIPFBPPQHQ-GDLZYMKVSA-N
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| InChi Code |
InChI=1S/C29H22ClN3O2/c1-4-19-6-5-7-20(14-19)24-16-28(34)33(3)26-13-10-22(15-25(24)26)29(35,27-17-31-18-32(27)2)21-8-11-23(30)12-9-21/h1,5-18,35H,2-3H3/t29-/m1/s1
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| 化学名 |
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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: ≥ 2.5 mg/mL (5.21 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 25.0 mg/mL澄清DMSO储备液加入到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: ≥ 2.5 mg/mL (5.21 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。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 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 | 2.0835 mL | 10.4175 mL | 20.8351 mL | |
| 5 mM | 0.4167 mL | 2.0835 mL | 4.1670 mL | |
| 10 mM | 0.2084 mL | 1.0418 mL | 2.0835 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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