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Therapeutic Effects of Chemical Inhibitors of AIMP2-DX2 and K-Ras Interaction on Lung Cancer : AIMP2-DX2와 K-Ras 단백질 간 결합 저해 물질의 폐암 치료 효과
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- Authors
- Advisor
- 김성훈
- Major
- 융합과학기술대학원 분자의학 및 바이오제약학과
- Issue Date
- 2018-02
- Publisher
- 서울대학교 대학원
- Keywords
- AIMP2-DX2 ; K-Ras ; lung cancer ; protein-protein interaction ; NanoBiT assay ; high-throughput screening (HTS)
- Description
- 학위논문 (석사)-- 서울대학교 대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과, 2018. 2. 김성훈.
- 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.
- Language
- English
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