Therapeutic Effects of Chemical Inhibitors of AIMP2-DX2 and K-Ras Interaction on Lung Cancer

Abstract

Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2-F) is a tumor suppressor which interacts with several factors regulating cell death and growth arrest. In contrast, AIMP2-DX2, a splicing variant missing exon 2 of AIMP2-F, enhances tumorigenesis in human lung or colorectal cancer through competitive inhibitory function of AIMP2-F. KRAS is proto-oncogene for making a protein called K-Ras protein that is involved in controlling cell division. When mutated, proto-oncogenes have the potential to cause normal cells to become cancerous. Especially, increase of mutated forms of K-Ras has been found in lung cancer patients. In previous study, AIMP2-DX2, an oncogenic variant of AIMP2, stabilizes K-Ras, and interaction of AIMP2-DX2 with K-Ras induced tumor growth. Therefore, we found therapeutic potential of interaction of AIMP2-DX2 with K-Ras in lung cancer treatment. Here we set up a cell-based Nano-luciferase binary technology (NanoBiT) to monitor the protein-protein interaction (PPI) between AIMP2-DX2 and K-Ras rapidly on 96-well scale. A total of 10000 compounds were screened for inhibitory activity on AIMP2-DX2 and K-Ras interaction, and 5 novel small molecule compounds were validated by various phenotypic experiments. Among those compounds, BC-DXI-27330 showed considerable lung cancer inhibitory efficacy in in vitro, cellular, and animal models. Through this research, we identified that the interaction between AIMP2-K-Ras is therapeutic target for human lung cancer and suggested effective small molecule compound as lung cancer medicine.