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Cancer is the 2nd leading cause of death in the US (>600K people died of cancer yearly), accounting for one in five deaths nationwide. Cancer has posed a high socioeconomic burden with an annual cost of > $200 billion. Novel approaches to target critical proteins in cancer biology are in desperate need and have been regarded as the foundation of precision medicine in cancer therapy. Protein modifications play a key role in regulating protein functions and signaling pathways. Among them, arginylation mediated by arginyl tRNA transferase 1 (ATE1) enzyme is a critical inhibition factor for cancer progression. Arginylation is considered a degradation signal called the Arg/N-degron pathway, thus, targeting arginylation for protein degradation has great promise in developing next-generation therapeutics.
Currently, arginylation and ATE1 are largely studied for their biological functions, their potential for therapeutic development on protein degradation remains unexplored. To develop novel therapeutic strategies based on arginylation, this project will use chemistry methods to bind and recruit ATE1 to oncoprotein targets. Using a combination of methods including AI-based virtual screening, experimental screening, and DNA encoded library (DEL) screening, we have obtained hit compounds of ATE1 binders. This project will further synthesize small molecules and their similar derivatives to investigate 1) their binding affinity with the protein, 2) their ability to inhibit the enzyme, 3) their biological activity in cellular models. Specific skills that can be learned from this project are chemical synthesis, thin-layer chromatography (TLC), mass spectrometry, nuclear magnetic resonance (NMR), drug design, and drug development. The student will also be exposed to lab’s research areas such as cell culture, proteomics, enzyme reaction, and proteomics data analysis.
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