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Design and Synthesis of Novel Anti-metastatic Hypoxic Cytotoxin TX-2137 Targeting AKT Kinase

Design and Synthesis of Novel Anti-metastatic Hypoxic Cytotoxin TX-2137 Targeting AKT Kinase

Ikkyu Shiba, Risa Kouzaki, Hisatsugu Yamada, Yoshio Endo, Takahisa Takino, Hiroshi Sato, Keiko Kitazato, Teruyoshi Kageji, Shinji Nagahiro, Yoshihiro Uto

Anticancer Res. 2017 Jul;37(7):3877-3883.

PMID: 28668889

Abstract:

Background:
The hypoxic microenvironment plays a crucial role in the malignant progression of tumor cells. Moreover, AKT, a serine/threonine kinase, is activated by various extracellular growth factors and is important for cell growth, survival, and motility of leukocytes, fibroblasts, endothelial cells, and tumor cells. Therefore, we aimed to design an anti-metastatic hypoxic cytotoxin which has inhibitory effects on AKT.
Results:
TX-2137 was designed and synthesized based on the structural similarity of a preexisting AKT1/2 kinase inhibitor and a hypoxic cytotoxin tirapazamine. TX-2137 effectively reduced the expression of phosphorylated AKT and matrix metalloproteinase 9 (MMP9) and showed strong inhibition of the proliferation of B16-F10, HT-1080, and MKN-45 cells. In addition, TX-2137 exhibited hypoxia-selective cytotoxicity towards A549 cells and inhibited liver metastasis of B16-F10 cells in a xenograft chick embryo model in the same way as doxorubicin.
Conclusion:
TX-2137 may be a potent lead compound in the development of a novel anti-metastatic AKT kinase inhibitor.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4241683	Akt1/2 kinase inhibitor			Price

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