Mubritinib (TAK 165)
(Synonyms: 木利替尼; TAK-165) 目录号 : GC10250
Mubritinib (TAK 165)是一种有效的选择性 HER2/ErbB2 抑制剂，其IC50为6nM。
Cas No.:366017-09-6
Sample solution is provided at 25 µL, 10mM.
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Mubritinib (TAK 165) is a potent, selective inhibitor of HER2/ErbB2 with IC50 of 6nM[1]. The erbB2 (also known as HER2 or neu) is a receptor tyrosine kinase with intrinsic tyrosine kinase activity[2]. When activated, HER2 provides the cell with potent proliferative and anti-apoptosis signals and it is the major driver of tumor development and progression[3]. Mubritinib is commonly used for research in cancers such as breast cancer, bladder cancer, and acute myeloid leukemia[4][5].
In vitro, BTSCs cells were treated with 500nM mubritinib for 24h, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSCs self-renewal and proliferation; flow cytometric quantitation showed a significant increase in the percentage of cells in the G1 phase and a decrease in the percentage of cells in the S phase in the mubritinib-treated BTSCs; gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27Kip1 pathway, leading to cell cycle impairment[6].
In vivo, in the xenograft model, after the tumor volume reached 100–150mm3 , mice were intraperitoneal injected with 100μl of mubritinib (10mg/kg, once a day) and 100μl of cisplatin (5mg/kg, once a week) for 18 days，and the combination therapy of mubritinib and cisplatin significantly reduced the mean volume and weight of grafts and inhibited the expression of Ki-67, PI3K, mTOR, and 4EBP1 in tumor tissues[7].
References:
[1] Nagasawa, J., Mizokami, A., Koshida, K., Yoshida, S., Naito, K., & Namiki, M. (2006). Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo. International journal of urology : official journal of the Japanese Urological Association, 13(5), 587–592.
[2] Tan, M., & Yu, D. (2007). Molecular mechanisms of erbB2-mediated breast cancer chemoresistance. Advances in experimental medicine and biology, 608, 119–129.
[3] Moasser M. M. (2007). The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene, 26(45), 6469–6487.
[4] Gutierrez, C., & Schiff, R. (2011). HER2: biology, detection, and clinical implications. Archives of pathology & laboratory medicine, 135(1), 55–62.
[5] Baccelli, I., Gareau, Y., Lehnertz, B., Gingras, S., Spinella, J. F., Corneau, S., Mayotte, N., Girard, S., Frechette, M., Blouin-Chagnon, V., Leveillé, K., Boivin, I., MacRae, T., Krosl, J., Thiollier, C., Lavallée, V. P., Kanshin, E., Bertomeu, T., Coulombe-Huntington, J., St-Denis, C., … Sauvageau, G. (2019). Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia. Cancer cell, 36(1), 84–99.e8.
[6] Burban, A., Tessier, C., Larroquette, M., Guyon, J., Lubiato, C., Pinglaut, M., Toujas, M., Galvis, J., Dartigues, B., Georget, E., Luchman, H. A., Weiss, S., Cappellen, D., Nicot, N., Klink, B., Nikolski, M., Brisson, L., Mathivet, T., Bikfalvi, A., Daubon, T., … Sharanek, A. (2025). Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile. EMBO molecular medicine, 17(3), 469–503.
[7] Dong, J., Zhu, D., Chen, M., Wang, T., Gao, Y., & Liu, W. (2022). Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function. Thoracic cancer, 13(10), 1513–1524.
Mubritinib (TAK 165)是一种有效的选择性 HER2/ErbB2 抑制剂，其IC50为6nM[1]。HER2（也称为 ErbB2 或 neu）是一种具有内在酪氨酸激酶活性的受体酪氨酸激酶[2]。当被激活时，HER2 为细胞提供强大的增殖和抗凋亡活性，是肿瘤发生和进展的主要驱动因素[3]。Mubritinib 常用于乳腺癌、膀胱癌和急性髓系白血病等癌症的研究[4][5]。
在体外实验中，BTSCs 细胞经 500nM mubritinib 处理 24 小时后，生物能量学检测和挽救实验表明，mubritinib靶向电子传递链的复合体 I，从而损害 BTSCs 的自我更新和增殖能力; 流式细胞术定量分析显示，细胞处于 G1 期的百分比显著增加，而处于 S 期的细胞百分比则减少; 基因表达分析和免疫印迹实验揭示，mubritinib扰乱了 AMPK/p27Kip1 通路，导致细胞周期受损[6]。
在体内实验中，在异种移植模型中，当肿瘤体积达到 100—150mm³ 后，小鼠腹腔注射 100μl mubritinib（10mg/kg，每日一次）和100μl cisplatin（5mg/kg，每周一次），持续18天，结果显示mubritinib和顺铂联合治疗显著降低了移植瘤的平均体积和重量，并抑制了肿瘤组织中 Ki-67、PI3K、mTOR 和 4EBP1 的表达[7]。
| Cell experiment [1]: | |
Cell lines | BTSCs cells |
Preparation Method | BTSCs were dissociated into single cell suspension using Accutase and 3 × 105 cells were plated in T25 flasks and treated with 500nM mubritinib (TAK 165) . After 24h, the cells were dissociated into single-cell suspensions, harvested and fixed with 70% ethanol overnight at 4°C. The cells were washed with 1X PBS and stained with FxCycle PI/RNase staining solution (Molecular Probes, #F10797) (Sharanek et al, 2021). The fluorescence was analysed by flow cytometry (Accuri C6 flow cytometer). The fractions of G0/G1-, S- and G2-phase cells were determined using the Watson pragmatic algorithm of FlowJo software. For gene expression profiling and Western blot analysis, cells were harvested for further investigation. |
Reaction Conditions | 500nM; 24h |
Applications | Mubritinib (TAK 165) impaired BTSCs self-renewal and proliferation, increased the percentage of cells in the G1 phase and decreased the percentage of cells in the S phase. Gene expression profiling and Western blot analysis revealed that mubritinib (TAK 165) disrupts the AMPK/p27Kip1 pathway, leading to cell cycle impairment. |
| Animal experiment [2]: | |
Animal models | male BALB/c-Nu mice |
Preparation Method | NCI-H1975 cells 2 ×106 were subcutaneously injected into the right flank of each mouse, and the growth of the transplanted tumor was continuously monitored. When the tumor volume reached 100–150mm3 , the mice were divided into four groups with five mice in each group: (1) control (Ctr): intraperitoneal injection of 100μl of PBS once a day; (2) cisplatin (Pt): intraperitoneal injection of 100 μl of cisplatin (5 mg/kg), once a week; (3) mubritinib (Mu): intraperitoneal injection of 100μl of mubritinib (10mg/kg), once a day for 18 consecutive days; and (4) combination (Com): combined injection of cisplatin and mubritinib as the monotherapy group. During treatment, the long and short diameters of the transplanted tumor were measured, and the volumes were calculated. At the end of the treatment, mice were sacrificed by inhalation of an overdose of ether. The tumor, heart, liver, spleen, lung, and kidney were dissected and fixed with formalin. |
Dosage form | 10mg/kg/day for 18 days; i.p. |
Applications | Combination therapy of mubritinib and cisplatin significantly reduced the mean volume and weight of grafts and inhibited the expression of Ki-67, PI3K, mTOR, and 4EBP1 in tumor tissues. |
References: | |
| Cas No. | 366017-09-6 | SDF | |
| 别名 | 木利替尼; TAK-165 | ||
| 化学名 | 4-[[4-[4-(triazol-1-yl)butyl]phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole | ||
| Canonical SMILES | C1=CC(=CC=C1CCCCN2C=CN=N2)OCC3=COC(=N3)C=CC4=CC=C(C=C4)C(F)(F)F | ||
| 分子式 | C25H23F3N4O2 | 分子量 | 468.47 |
| 溶解度 | ≥ 76.9mg/mL in DMSO with gentle warming | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1346 mL | 10.673 mL | 21.3461 mL |
| 5 mM | 0.4269 mL | 2.1346 mL | 4.2692 mL |
| 10 mM | 0.2135 mL | 1.0673 mL | 2.1346 mL |
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