Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Japan
Tumor cells adapt and reprogram their metabolic machinery to environmental conditions. The metabolic pathway specific to the tumor cells different from the normal cells should be a successful target for new antitumor compounds. In my presentation, I will talk on the construction of screening system for inhibitors targeting tumor metabolism as the first part. The bioenergetic 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 the tumor metabolism inhibitors. In the course of the screening from our chemical library, we found that NPD2381. As 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. Furthermore, RKN2381 increased the level of enzymes within the serine biosynthesis pathway (SBP) such as phosphoglycerate dehydrogenase (PHGDH). In addition, we found that serine depletion in certain tumor cells with limited serine synthesis plasticity increased the sensitivity to the mitochondrial inhibitors. We demonstrated that NPD2381 inhibited cancer stemness and tumorspheres of cancer stem cells like (iCSCL) cells.