Study on small-molecule modulators of pancreatic cancer metabolism

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K16563
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Kawamura Tatsuro 国立研究開発法人理化学研究所, 環境資源科学研究センター, 協力研究員 (60528561)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: すい臓がん / 代謝 / 活性酸素種 / MTH1

Outline of Final Research Achievements

Pancreatic cancer is a highly aggressive disease, and development of more effective therapy is desired. In the present study, we identified two compounds which modulate metabolism of pancreatic cancer cells. Compound A inhibits mitochondrial respiration chain complex III, and Compound B inhibits glycolysis.
On the other hand, MTH1 is a hydrolase of oxidized purine nucleoside triphosphates, which attracted attention as a potential cancer therapeutic target. Recently, we identified new MTH1 inhibitors by chemical array screening. Proteomic profiling of small-molecule inhibitors revealed mechanistic differences among chemically distinct MTH1 inhibitors. In addition, overexpression of MTH1 did not rescue cells from MTH1 inhibitor-induced cell death, and siRNA-mediated knockdown of MTH1 did not suppress cancer cell growth. Taken together, we conclude that the cytotoxicity of MTH1 inhibitors is attributable to off-target effects and that MTH1 is not essential for cancer cell survival.

Free Research Field

ケミカルバイオロジー