The majority of human proteome is considered intractable to conventional drug discovery efforts. Our laboratory aims to develop small molecule therapeutic approaches that modulate disease pathways or targets in unique ways. Our interdisciplinary research program integrates proteomics, biochemistry, cell biology and organic synthesis, and is currently focusing on the following aspects.
1. New drug modalities
Conventional small molecule drugs function by directly disrupting the activities of proteins. However, many proteins lack functional pockets that are amenable to rational drug design and are considered difficult to target with small molecules, or even “undruggable.” Our research employs chemical biology techniques and chemical proteomic technologies to uncover new drug modalities, such as protein degraders, activators, and stabilizers, which alter protein functions through novel mechanisms, thereby expanding the druggable space within the human proteome.
2. Cancer neoantigens
Cancer immunotherapy, which utilizes the body’s own T cells to destroy cancer cells, has shown therapeutic efficacy in patients with various forms of cancer. Cancer neoantigens, the primary target of tumor-specific T cells, are major histocompatibility complex I (MHC-I)-presented peptides that originate from genetically mutated forms of proteins. Our research combines chemical tools, proteomic platforms, and molecular biology approaches to uncover druggable opportunities targeting the cancer neoantigen processing and presentation pathway.
3. E3 ubiquitin ligases
E3 ubiquitin ligases regulate protein homeostasis by facilitating or catalyzing ubiquitination on protein substrates, thereby promoting substrate degradation. The human genome contains over 600 E3 ubiquitin ligases, many of which have been associated with various diseases. Our research employs biochemistry, proteomics, and cell biology techniques to investigate the biological functions of E3 ubiquitin ligases, with a particular focus on those that have been genetically linked to cancer progression but have not yet been biochemically characterized.
4. Functional proteomics
We integrate functional assays with proteomics to simultaneously identify small molecules that exhibit a specific phenotype and determine how they function. Additionally, we develop chemical proteomic platforms to quantitatively and specifically measure small molecule-protein interactions on a proteome-wide scale.
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