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

doi:10.21873/anticanres.11768

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

Anticancer Res. 2017 Jul;37(7):3877-3883. doi: 10.21873/anticanres.11768.

Authors

Affiliations

¹ Graduate School of Advanced Technology and Science, Tokushima University, Tokushima, Japan.
² Institute of Technology, Industrial and Social Sciences, Tokushima University Graduate School, Tokushima, Japan.
³ Central Research Resource Branch, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
⁴ Institute of Liberal Arts and Science, Kanazawa University, Kanazawa, Japan.
⁵ Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
⁶ Institute of Technology, Industrial and Social Sciences, Tokushima University Graduate School, Tokushima, Japan uto.yoshihiro@tokushima-u.ac.jp.

PMID: 28668889
DOI: 10.21873/anticanres.11768

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.

Keywords: AKT; TX-2137; anti-metastatic agent; hypoxic cytotoxin.

MeSH terms

A549 Cells
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Hypoxia / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chick Embryo
Drug Design
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / secondary
Matrix Metalloproteinase 9 / metabolism
Mice
Neoplasm Metastasis
Phosphorylation / drug effects
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Matrix Metalloproteinase 9