Entrectinib
(Synonyms: 恩曲替尼; NMS-E628; RXDX-101) 目录号 : GC14476
Entrectinib是一种具有口服活性、可穿透血脑屏障（BBB）且在中枢神经系统起作用的TrkA/B/C、ROS1与ALK抑制剂，其IC50值分别为1、3、5、12和7nM。
Cas No.:1108743-60-7
Sample solution is provided at 25 µL, 10mM.
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Entrectinib is an orally active, blood brain barrier(BBB)-penetrated and centrally active inhibitor of TrkA/B/C, ROS1 and ALK, with IC50 values of 1, 3, 5, 12 and 7nM, respectively[1]. TrkA/B/C are neurotrophin receptors, ROS1 is an orphan receptor tyrosine kinase, and ALK is an anaplastic lymphoma kinase; all three drive tumorigenesis through fusion or mutation[2]. Entrectinib is commonly used in the study of ROS1-rearranged non-small cell lung cancer (NSCLC) and NTRK fusion-positive solid tumors[3].
In vitro, Entrectinib (2.3-4.3μM; 48h) dose-dependently reduced viability, suppressed colony formation and EdU incorporation, and elevated apoptosis in PC12, HT22 and SK-N-SH nerve cells, with cellular IC50 values of 2.3, 4.2 and 4.3μM, respectively[4]. Entrectinib (100-400nM; 24h) dose-dependently inhibited TGF-β1-driven proliferation, migration, and myofibroblast activation of Mlg and HFL1 lung fibroblasts and blocked TGF-β1-induced epithelial-mesenchymal transition (EMT) in MLE12 epithelial cells[5].
In vivo, Entrectinib (60mg/kg; BID for 7 weeks; p.o.) markedly suppressed SY5Y-TrkB xenograft growth, prolonged mouse event-free survival, and blocked TrkB, Akt and Erk phosphorylation in athymic nu/nu mice[6]. Entrectinib (10mg/kg; i.p.) reduced LPS-induced serum IL-1β and hepatic AST/ALT levels, and improved 24h survival in C57BL/6J mice[7].
References:
[1] Ardini E, Menichincheri M, Banfi P, et al. Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016;15(4):628-639.
[2] Drilon A, Siena S, Ou SI, et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400-409.
[3] Osman HM, Tuncbilek M. Entrectinib: A New Selective Tyrosine Kinase Inhibitor Approved for the Treatment of Pediatric and Adult Patients with NTRK Fusionpositive, Recurrent or Advanced Solid Tumors. Curr Med Chem. 2022;29(15):2602-2616.
[4] Tang Q, Dong J, Zhang F, et al. Entrectinib can induce nerve cell damage by inhibiting PI3K-AKT and TGF-β signaling pathways. Front Pharmacol. 2025;16:1489210.
[5] Miao Y, Li X, Yang Y, et al. Entrectinib ameliorates bleomycin-induced pulmonary fibrosis in mice by inhibiting TGF-β1 signaling pathway. Int Immunopharmacol. 2022;113(Pt B):109427.
[6] Iyer R, Wehrmann L, Golden RL, et al. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016;372(2):179-186.
[7] Jin X, Liu D, Zhou X, Luo X, Huang Q, Huang Y. Entrectinib inhibits NLRP3 inflammasome and inflammatory diseases by directly targeting NEK7. Cell Rep Med. 2023;4(12):101310.
Entrectinib是一种具有口服活性、可穿透血脑屏障（BBB）且在中枢神经系统起作用的TrkA/B/C、ROS1与ALK抑制剂，其IC50值分别为1、3、5、12和7nM[1]。TrkA/B/C是神经营养因子受体，ROS1为孤儿受体酪氨酸激酶，ALK则是一种间变性淋巴瘤激酶；三者均可通过基因融合或突变驱动肿瘤发生[2]。Entrectinib常用于 ROS1 重排的非小细胞肺癌（NSCLC）以及 NTRK 融合阳性实体瘤的研究[3]。
体外实验中，Entrectinib（2.3-4.3μM；48h）可剂量依赖性地降低PC12、HT22 与 SK-N-SH神经细胞活力，抑制集落形成和 EdU 掺入，并诱导细胞凋亡，其细胞水平 IC50分别为2.3、4.2和4.3μM[4]。Entrectinib（100-400nM；24h）亦可剂量依赖性地抑制TGF-β1诱导的Mlg和HFL1肺成纤维细胞增殖、迁移及肌成纤维细胞活化，并阻断MLE12上皮细胞的TGF-β1诱导的上皮-间充质转化（EMT）[5]。
体内实验中，Entrectinib（60mg/kg；每日两次，持续7周；口服）显著抑制SY5Y-TrkB异种移植瘤生长，延长小鼠无事件生存期，并在裸鼠中阻断TrkB、Akt与Erk的磷酸化[6]。Entrectinib（10mg/kg；腹腔注射）可降低C57BL/6J小鼠LPS诱导的血清IL-1β及肝脏AST/ALT水平，并提高24小时存活率[7]。
| Cell experiment [1]: | |
Cell lines | PC12, HT22 and SK-N-SH cells |
Preparation Method | The rat adrenal pheochromocytoma cells PC12(FH0415) cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and 1% penicillin and streptomycin. mouse hippocampal neuron cells HT22 (FH1027) and human neuroblastoma cells SK-N-SH (FH0164) were cultured in DMEM mediumwith 10% FBS and 1% penicillin and streptomycin. All cells were incubated in a 37°C with 5% CO2 atmosphere. To explore whether Entrectinib influences the cellular proliferation ability and apoptosis, cells were treated with 2.3, 4.2 and 4.3μM Entrectinib for 48h, respectively. After incubation, 10μL CCK-8 solution was added into each well and incubated at 37°C for 2h in the dark. Then, a microplate reader was used to measure the absorbance at a wavelength of 450nm. EdU cell proliferation detection kit was used for cell proliferation detection. Annexin V-FITC/PI kit was used for cell apoptosis analysis. |
Reaction Conditions | 2.3-4.3μM; 48h |
Applications | Entrectinib dose-dependently reduced viability, suppressed EdU incorporation, and elevated apoptosis in PC12, HT22 and SK-N-SH nerve cells. |
| Animal experiment [2]: | |
Animal models | athymic nu/nu mice |
Preparation Method | Six-week-old athymic nu/nu mice were obtained from Jackson Laboratories. Mice were maintained at five per cage under humidity- and temperature-controlled conditions in a light/ dark cycle that was set at 12h intervals. For the xenograft studies, animals were injected subcutaneously in the flank with 1×107 SY5Y-TrkB cells in 0.1ml of Matrigel. Tumors were measured 2 times per week in 3 dimensions, and the volume calculated as follows: [(0.523xLxWxW)/1000]. Body weights were measured at least twice a week, and the dose of compound was adjusted accordingly. Treatment with Entrectinib, Irino and TMZ started about 15–17 days after tumor inoculation when the average tumor size was 0.2cm3. Entrectinib was dosed at 60mg/kg BID by gavage for the entire duration of the study(7 weeks). After the final dose was given, the blood samples were drawn from 4 mice per time point via retro-orbital bleeding and collected in heparinized tubes on wet ice. The plasma was then separated by centrifugation at 1200g for 10 minutes at 4°C. The pharmacokinetic analysis was performed using the Watson system. Mice were sacrificed when tumor volume reached 3cm3 . Tumors were harvested and flash frozen on dry ice for analysis of protein expression using Western blot. |
Dosage form | 60mg/kg; BID for 7 weeks; p.o. |
Applications | Entrectinib markedly suppressed SY5Y-TrkB xenograft growth, prolonged mouse event-free survival, and blocked TrkB, Akt and Erk phosphorylation in athymic nu/nu mice. |
References: | |
| Cas No. | 1108743-60-7 | SDF | |
| 别名 | 恩曲替尼; NMS-E628; RXDX-101 | ||
| 化学名 | (Z)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3(2H)-ylidene)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide | ||
| Canonical SMILES | CN1CCN(C2=CC(NC3CCOCC3)=C(C(/N=C4C5=C(NN/4)C=CC(CC6=CC(F)=CC(F)=C6)=C5)=O)C=C2)CC1 | ||
| 分子式 | C31H34F2N6O2 | 分子量 | 560.64 |
| 溶解度 | ≥ 28.05mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 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 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7837 mL | 8.9184 mL | 17.8368 mL |
| 5 mM | 356.7 μL | 1.7837 mL | 3.5674 mL |
| 10 mM | 178.4 μL | 891.8 μL | 1.7837 mL |
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