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]。