TAK-165 is also named as mubritinib which is first originally designed and synthesized by Takeda Chemical Industries in Japan. Mubritinib (TAK 165) (view Fig. 1 for its chemical structure) is validated as a potent human epidermal growth factor receptor 2 (HER2; erbB2) that is classified into one of members of epidermal growth factor receptor tyrosine kinase family, inhibitor with an IC50 of 6nM for the HER2. Many lines of evidences that human epidermal growth factor receptor 2 (HER2) is expressed in bladder cancer cell lines (such as, HT1376, UMUC3 and T24), renal cell carcinoma (RCC) cell lines (ACHN) and androgen-independent prostate cancer cell lines (DU145, LNCaP, LN-REC4) has been reported. However, The results of western blot analysis showed that the expression levels of human epidermal growth factor receptor 2 (HER2) in these cancer cell lines was weak compared with that in breast cancer cell lines BT474 which highly expressed HER2. For the investion of in vitro effectiveness, Mubritinib (TAK-165) treated cells mentioned above for 72 hours at different concentrations. Then the number of cells was counted with a hemocytometer for calculation of IC50 value of TAK-165 against cell lines. The results suggested that TAK-165 blocked the phosphorylation of HER2 and sequentially inhibit its down-stream Akt and MAPK in HER2 strongly expressing BT474 breast cancer. As we known, human epidermal growth factor receptor 2 (HER2) activates its downstream PI3K and MAPK signaling transduction pathways that are associated with apoptosis and growth of cells, respectively. At a low concentration of 0.1 M, the phosphorylation of HER2 was sufficiently prevented by TAK-165 as well as that of Akt and MAPK. Lots of Src-Bcr-Abl inhibitors have been presented from multitargeted ones (including AT9283, Dasatinib (BMS-354825), NVP-BHG712, Ponatinib (AP24534) and PP-121 et al.) to specific ones (e.g. Nilotinib (AMN-107), Bosutinib (SKI-606) and Bafetinib(INNO-406) et al.) in previous two blogs. Their chemical structures and primary biological properties were displayed. Here, another group of Src-Bcr-Abl inhibitors (including quercetin, saracatinib (AZD0530), WP1130) were introduced as follows. Quercetin[1] (Fig. 1) is a potent PI3K and PKC signaling pathway inhibitor with IC50 of 3.8 M and 15g/ml. The molecular weight of quercetin is C15H10O7 and its formula is 302.24. The activities of PI3K and Src kinases were strongly inhibited by quercetin, while the activities of Akt1/2 PKC, p38 and ERK1/2 kinases were mildly or slightly affected. Fig. 1 The chemical structure of quercetin Saracatinib (AZD0530)[2] (Fig. 2) is a highly selective, orally available, dual-specific Src/Abl kinase inhibitor with IC50 of 2.7 and 30 nM for c-Src and Abl kinase, respectively. The molecular weight of saracatinib (AZD0530) is C27H32ClN5O5 and its formula is 542.03. Saracatinib (AZD0530) has high selectivities for Src and Abl kinases against a large range of tyrosine and serine- threonine kinases (VEGFR2, FGFR, c-Kit and Aur-3 etc. IC50 >5 M) Fig. 2 The chemical structure of saracatinib (AZD0530) WP1130 (Fig. 3) is a novel selective small molecular deubiquitinase inhibitor and a Bcr/Abl destruction pathway activator with an IC50 of 1.8 M for K562 cells. The molecular weight of WP1130 is C19H18BrN3O and its formula is 384.27. WP1130 specifically and rapidly decreased the expression of both wild-type and mutant Bcr/Abl protein but not affected the expression of bcr/abl gene in chronic myelogenous leukemia (CML) cells. Fig. 3 The chemical structure of WP1130 References: [1] Eur J Med Chem. 2009 May;44(5):1982-8. [2] Clin Breast Cancer. 2011 May 3.
Please Rate this Article 5 out of 54 out of 53 out of 52 out of 51 out of 5
Not yet Rated
