Development of small-molecule inhibitors targeting the metabolic switch in cancer cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K05744
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Kawatani Makoto 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, 専任研究員 (50391925)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: がん / 代謝 / 阻害剤

Outline of Final Research Achievements

The metabolic adaptation of cancer cells is considered to be a promising therapeutic target, but the switching mechanism of energy metabolism remains unclear. We found that the glucose transporter GLUT1 knockout colon cancer DLD1 cells (GLUT1-/- cells) showed a large shift in energy metabolism from glycolysis to oxidative phosphorylation compared to the wild-type cells (WT cells). Quantitative proteomic analysis of GLUT1-/- and WT cells identified several proteins that may be involved in the metabolic switch. We performed chemical array-based screening for those proteins and obtained several hit compounds. Furthermore, we found that NPD403-5, which was obtained by cell-based screening targeting cancer cell metabolism, targets GLUTs and exhibits significant antitumor activity in vivo.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

がん細胞は、周囲の環境に応じて代謝を巧みに適応させることで、旺盛な増殖や過酷な条件下での生存を支えている。このような生存のための代謝適応は、がん治療の有望な標的になると考えられるが、エネルギー代謝のスイッチ分子や制御機構は不明な点が多いのが現状である。本研究で得られた代謝スイッチに関わる可能性のあるタンパク質に作用する小分子化合物は、がん細胞のエネルギー代謝スイッチ機構を理解する有用なツールになる。さらに、今後抗がん剤としての有用性を示せれば、がん特異的な代謝機構を標的とした新たな治療法の確立にもつながることが期待される。