Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
Tumor cells adapt and reprogram their metabolic machinery to environmental conditions. The metabolic pathway specific to tumor cells and different from normal cells should be a successful target for new antitumor compounds. In the first part of my presentation, I will talk about the construction of a screening system for inhibitors targeting tumor metabolism. The bio-energetic parameters focusing on two major metabolic phenotypes, OCR (oxygen consumption rate) and ECAR (extracellular acidification rate), were measured after treatment with drug candidates to explore tumor metabolism inhibitors. The screening of our chemical library yielded several hit compounds including NPD2381.
For the last part of my presentation, I will explain the multidimensional target identification system integrating metabolome analysis and proteome analysis. NPD2381 showed the phenotype of mitochondrial respiration inhibition. Moreover, it increased the level of enzymes within the serine biosynthesis pathway (SBP) such as phosphoglycerate dehydrogenase (PHGDH). Interestingly, serine depletion in certain tumor cells increased the sensitivity to mitochondrial inhibitors. Taken together, NPD2381 inhibited cancer stemness and the growth of the spheroid culture of cancer cells.