The majority of the human proteome is considered intractable to conventional drug discovery efforts. Our lab seeks to develop small molecule therapeutic modalities that modulate disease pathways or targets in different ways from conventional occupancy-driven small molecule therapies. Our interdisciplinary research program integrates proteomics, biochemistry, cell biology and organic synthesis, and is currently focused on the following aspects.
1. New drug modalities
Conventional small molecule drugs act by directly perturbing the functions of proteins. Many proteins, however, lack functional pockets for rational drug design and are considered challenging to target with small molecules, or even ‘undruggable’. We utilize chemical biology approaches and chemical proteomic technologies to discover new drug modalities, such as protein degraders, activators, and stabilizers, that alter protein functions through novel mechanisms, therefore expanding druggable space in human proteome.
2. Cancer neoantigens
Cancer immunotherapy that harnesses endogenous T cells to destroy cancer cells has demonstrated dramatic therapeutic efficacy in patients with various types of cancer. Cancer neoantigens, the prime target of tumor-specific T cells, are major histocompatibility complex I (MHC-I)-presented peptides and generated from genetically mutated forms of proteins. In this direction, we integrate chemical tools, proteomic platforms and molecular biology approaches to discover druggable opportunities targeting cancer neoantigen processing and presentation pathway.
3. E3 ubiquitin ligases
E3 ubiquitin ligases control protein homeostasis by assisting or catalyzing ubiquitination on the protein substrate, therefore promoting substrate degradation. The human genome encodes 600+ E3 ubiquitin ligases, many of which have been linked to various diseases. We utilize biochemistry, proteomic and cell biology approaches to investigate the biological functions of E3 ubiquitin ligases, especially those that have been genetically linked to cancer progression but have not been biochemically characterized.
4. Functional proteomics
We integrate functional assays with proteomics to simultaneously discover phenotypically active small molecules and deconvolute their mechanism-of-action. We also develop chemical proteomic platforms to quantitatively and site-specifically measure small molecule-protein interactions on a proteome-wide scale.