Nomura Research Group
The Nomura Research Group is focused on developing and applying chemical proteomic and metabolomic platforms to identify and pharmacologically target metabolic drivers of human disease. Our laboratory currently has three major research areas. Our first research area focuses on developing and applying chemoproteomic and metabolomic platforms to map metabolic drivers of complex human diseases, including cancer, neurodegenerative diseases, and inflammatory disorders, towards developing novel therapeutic strategies to cure these complex human pathologies. Our second research area focuses on developing chemoproteomic tools and technologies to map proteome-wide hyper-reactive and ligandable hotspots towards massively expanding our capability of developing pharmacological tools and eventually therapeutics against the entirety of the proteome. Our third research area is around developing innovative chemoproteomic and metabolomic strategies for comprehensive assessment of chemical toxicology ranging from small-molecule target identification, target characterization, and predictive and mechanistic toxicological assessment.
Mapping Metabolic Drivers of Cancer. Cancer cells possess fundamentally altered cellular metabolism that not only leads to a re-wiring of cellular biochemistry, but also drives nearly every aspect of cancer pathogenicity. While targeting dysregulated metabolism is a promising strategy for cancer treatment, much of research in cancer metabolism has focused on well-understood metabolic pathways in central carbon metabolism underlying cellular transformation and early-stages of cancer, and has largely ignored the majority of cellular metabolic pathways or those networks involved in cancer progression, despite clear genetic or metabolic evidence of their involvement in cancer. This is in-part because our efforts are hindered by our largely incomplete understanding of metabolic networks in normal physiology, let alone in human cancers. This includes the large number of uncharacterized or misannotated metabolic enzymes, undiscovered metabolites, and orphan metabolic networks. Historically, scientists have shied away from uncovering the oncological roles of these uncharacterized enzymes and metabolic pathways, leaving untapped the large therapeutic potential that remains in the majority of the unexplored metabolic genome. A major focus of our research group is to massively expand the arsenal of targets, mechanisms, and drugs to combat cancer by mapping the unexplored and untapped novel metabolic drivers of cancer using chemoproteomic and functional metabolomic platforms. We have already made substantial progress towards this goal by using integrated platforms that incorporate: 1) activity-based protein profiling (ABPP) platform, which uses active-site directed chemical probes coupled to proteomics to enrich, detect, and quantify dysregulated metabolic enzyme activities en masse in cancer; 2) functional targeted and discovery-based metabolomic platforms to identify novel dysregulated metabolic pathways and functionally annotate the metabolic and pathophysiological roles of cancer-relevant enzymes; and 3) a competitive ABPP inhibitor/drug-discovery platform based on competing small-molecule inhibitors against activity-based probe binding to enzyme active sites to discover potent, selective, and in vivo active compounds for further biological validation.
Using Reactivity-Based Chemoproteomic Platforms to Expand the Druggable Proteome through High-Throughput Pharmacological Mapping of Ligandable Sites. Despite the completion of human genome sequencing efforts nearly 15 years ago and the promise of genome-based discoveries that would cure human diseases, more than 75% of all protein research still focuses on the same 10% of proteins characterized before the sequencing of the human genome. Even with the identification of many novel protein targets that control disease, these potential drug targets have remained largely untranslated, in-part because most protein targets are “undruggable,” and the majority of the proteome is devoid of pharmacological tools, hindering and oftentimes paralyzing translational research efforts in drug discovery. Development of high-quality chemical tools for proteins catalyzes research into the function and therapeutic exploitation of those proteins, thus correlating the development of chemical tools for specific proteins with their associated research activity. Thus, developing pharmacological tools for every protein in the proteome would radically expand our ability to understand protein function, mine the entirety of the proteome for drug targets, and accelerate the drug discovery process to cure complex diseases. However, “drugging” all proteins simultaneously, has remained practically impossible. Furthermore, assessing the quality and selectivity of small-molecule modulators of protein function has remained challenging. We have been using the reactivity-based chemoproteomic platforms to enable simultaneous high-throughput discovery of small-molecule leads for drug discovery across the entire proteome by globally profiling and pharmacologically interrogating proteome-wide hyper-reactive hotspots. We have been combining the screening of reactive small-molecule fragment libraries against the profiling of proteome-wide hyper-reactive hotspots with reactivity-based probes directly in complex proteomes to enable: 1) the identification of proteome-wide hyper-reactive and functional hotspots with reactivity-based probes, which in-turn serve as sites that can be pharmacologically interrogated; 2) accelerated and massively parallel development of small-molecule modulators of large numbers of protein targets and the assessment of their proteome-wide selectivity; and 3) chemical genomics coupled with facile target identification to identify novel therapeutic targets.
Mapping Proteome-Wide Interactions of Environmental Chemicals to Uncover Novel Toxicological Mechanisms. We are environmentally exposed to countless synthetic chemicals on a daily basis, with an increasing number of these chemical exposures linked to adverse health effects. However, our understanding of the (patho)physiological effects of these chemicals remains poorly understood, due in part to a general lack of effort to systematically and comprehensively identify the direct interactions of environmental chemicals with biological macromolecules in mammalian systems in vivo. Understanding the direct protein targets of chemicals provides critical information on the types of biochemical and (patho)physiological effects that may be expected from exposure to the chemical. Our lab has been using activity-based and reactivity-based chemoproteomic strategies to comprehensively identify chemical-protein interactions in complex biological systems, which has in-turn allowed us to identify unique and novel toxicological mechanisms for many widely used chemicals in our environment.