Our Research

Research Overview

The Nomura Research Group is focused on redefining druggability using chemoproteomic platforms to discover new cancer therapies. We are a highly interdisciplinary research group with expertise in chemical biology, synthetic chemistry, biochemistry, cancer biology, metabolism, proteomics, and metabolomics.

Major Research Directions

  1. Chemoproteomics-enabled covalent ligand discovery against druggable hotspots for cancer therapy
  2. Covalent ligand discovery against druggable hotspots targeted by natural products to discover new targets and drugs for cancer therapy
  3. Mapping metabolic drivers of cancer using chemoproteomic and metabolomic platforms
  4. Coupling chemoproteomics-enabled covalent ligand discovery with targeted protein degradation strategies to proteosomally degrade undruggable targets
  5. Discovering new toxicological mechanisms of environmental and pharmaceutical chemicals using chemoproteomic platforms

Chemo-Proteomics

Covalent Ligand Screening to Map Druggable Hotspots

Mapping Druggable Hotspots Targeted by Natural Products

Chemical Proteomics and Targeted Protein Degradation

Disease Therapies

Nomura Research Group

The Nomura Research Group is focused on developing and applying chemoproteomic and metabolomic platforms to discover new therapeutic targets and therapies for cancer. We currently have five major research directions. Our first research area focuses on coupling screening of fragment-based covalent ligand libraries with chemoproteomic platforms to discover novel druggable hotspots that can be targeted for cancer therapy. Our second research area focuses on covalent ligand discovery against druggable hotspots targeted by covalently-acting anti-cancer natural products using chemoproteomic platforms to discover new therapeutic targets and synthetically tractable therapies for cancer. Our third research area focuses on developing and applying chemoproteomic and metabolomic platforms to discover, characterize, and pharmacologically target metabolic drivers of cancer. Our fourth research area focuses on coupling chemoproteomics-enabled covalent ligand discovery platforms with targeted protein degradation strategies to pharmacologically target and proteosomally degrade undruggable proteins. Our fifth research area is focused on using chemoproteomic platforms to map proteome-wide targets and off-targets of pharmaceutical and environmental chemicals towards discovering new mechanisms of biological action and toxicity.

Chemoproteomics-enabled covalent ligand discovery to map druggable hotspots for cancer therapy. Even with the identification of many novel protein targets that control cancer, these potential cancer therapy targets have remained largely untranslated, in-part because most of these proteins are “undruggable” or difficult to target with small-molecules. Developing technologies that enable the coupled discovery of new cancer targets and small-molecule therapies would provide a disruptive and innovative platform to discover next-generation cures for cancer. Recently, chemoproteomic technologies have arisen to address this challenge, including isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP), which uses reactivity-based probes to map proteome-wide reactive, functional, and druggable hotspots directly in complex proteomes. When used in a competitive manner, covalently-acting small-molecules can be competed against the binding of reactivity-based probes to druggable hotspots directly in complex proteomes to enable inhibitor discovery against undruggable targets using the isoTOP-ABPP platform. To facilitate the discovery of new anti-cancer therapeutic leads and targets, we have been screening our covalent ligand libraries to discover anti-cancer agents and have then been using our isoTOP-ABPP platforms to map the specific druggable hotspots targeted by our anti-cancer leads. Through this coupled strategy, we have discovered many new small-molecule leads and targets for cancer therapy. Publications on this topic can be found below:

  1. Grossman E*, Ward CC*, Spradlin JN, Bateman LA, Huffman TR, Miyamoto DK, Kleinman JI, Nomura DK. (2017) Covalent ligand discovery against druggable hotspots targeted by anti-cancer natural products. In press at Cell Chemical Biology. (*co-first authorship)
  2. Anderson KE, To M, Olzmann JA, Nomura DK. (2017) Chemoproteomics-enabled covalent ligand screening reveals a thioredoxin-caspase 3 interaction disruptor that impairs breast cancer pathogenicity. ACS Chemical Biology doi: 10.1021/acschembio.7b00711. PMID 28892616
  3. Bateman LA#, Nguyen TB#, Roberts AM#, Miyamoto DK, Ku W-M, Huffman TR, Heslin MJ, Contreras CM, Skibola CF, Olzmann JA*, Nomura DK*. (2017) Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in Reticulon 4 that impairs ER morphology and cancer pathogenicity. Chemical Communications doi: 10.1039/C7CC01480E. PMID 28352901(#co-first authors; *co-corresponding author)
  4. Roberts AM, Miyamoto DK, Huffman TR, Bateman LA, Ives AN, Akopian D, Heslin MJ, Contreras CM, Rape M, Skibola CF, Nomura DK. (2017) Chemoproteomic screening of covalent ligands reveals UBA5 as a novel pancreatic cancer target. ACS Chemical Biology 12, 899-904. PMID 28186401
  5. Roberts AM, Ward CC, Nomura DK. (2017) Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots. Current Opinion in Biotechnology 43, 25-33. PMID 27568596

Covalent ligand discovery against druggable hotspots targeted by covalently-acting anti-cancer natural products. Natural products isolated from microbes, plants, and other living organisms have been a tremendous source of cancer therapeutics and comprise about 50 % of the drugs that are used for cancer chemotherapy. While there are countless additional natural products that have been shown to have anti-cancer activities, there are major bottlenecks associated with developing natural products as anti-cancer therapies. First, many of these drugs have been difficult to isolate in large quantities from their biological sources and have been challenging to synthesize. Second, the direct targets and mechanisms of action of most anti-cancer natural products remain poorly understood. Among these natural products are agents that contain potential reactive electrophilic centers that can covalently react with nucleophilic amino acid hotspots on proteins to modulate their biological action. We believe that identifying the direct targets and mechanisms of anti-cancer natural products would not only enable the discovery of unique druggable hotspots that can be targeted for cancer therapy, but also enable pharmacological interrogation of these targets using covalent ligand discovery approaches to uncover more synthetically accessible leads for cancer therapy. Our lab has been using isoTOP-ABPP chemoproteomic platforms to map druggable hotspots targeted by covalently-acting anti-cancer natural products to discover new cancer therapy targets. We have then been interrogating these sites with libraries of covalent ligands to generate more synthetically tractable lead compounds that target the same sites. Publications on this topic are below and more are forthcoming:

  1. Grossman E*, Ward CC*, Spradlin JN, Bateman LA, Huffman TR, Miyamoto DK, Kleinman JI, Nomura DK. (2017) Covalent ligand discovery against druggable hotspots targeted by anti-cancer natural products. In press at Cell Chemical Biology. (*co-first authorship)
  2. Roberts LS, Yan P, Bateman LA, Nomura DK. (2017) Mapping novel metabolic nodes targeted by anti-cancer drugs that impair triple-negative breast cancer pathogenicity. ACS Chemical Biology 12, 1133-1140. PMID 28248089

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 focus of our research group is to 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. Publications on this topic can be found below:

  1. Roberts LS, Yan P, Bateman LA, Nomura DK. (2017) Mapping novel metabolic nodes targeted by anti-cancer drugs that impair triple-negative breast cancer pathogenicity. ACS Chemical Biology 12, 1133-1140. PMID 28248089
  2. Bateman LA, Ku W-M, Heslin MJ, Contrearas CM, Skibola CF, Nomura DK. (2017) ASS1 is an important metabolic regulator of colorectal cancer. ACS Chemical Biology 12, 905-911. PMID 28229591
  3. Kohnz RA, Roberts, LS, DeTomaso D, Badyopadhyay S, Yosef N, Nomura DK. (2016) Protein sialylation regulates a gene expression signature that promotes breast cancer cell pathogenicity. ACS Chemical Biology 11, 2131-2139. PMID 27380425
  4. Louie SM, Grossman EA, Crawford LA, Ding L, Camarda R, Huffman TR, Miyamoto DK, Goga A, Weerapana E, Nomura DK. (2016) GSTP1 is a driver of triple-negative breast cancer cell metabolism and pathogenicity. Cell Chemical Biology 5, 567-578. PMID 27185638
  5. Benjamin DI, Li DS, Lowe, W, Heuer T, Kemble G, Nomura DK. (2015) Diacylglycerol metabolism and signaling is a predictive and driving force underlying FASN inhibitor sensitivity in cancer cells. ACS Chemical Biology 10, 1616-1623. PMID: 25871544
  6. Mulvihill MM, Benjamin DI, LeScolan E, Ji X, Shieh A, Green M, Narasimhalu T, Morris PJ, Luo K, Nomura DK. (2014) Metabolic Profiling Reveals PAFAH1B3 as a critical driver of breast cancer pathogenicity. Chemistry & Biology 21, 831-840. PMID: 24954006
  7. Benjamin DI, Louie S, Mulvihill MM, Kohnz RA, Li DS, Chan LG, Sorrentino A, Bandhyopadhyay S, Cozzo A, Ohiri A, Goga A, Ng-SW, Nomura DK. (2014) Inositol phosphate recycling regulates glycolytic and lipid metabolism that drives cancer aggressiveness. ACS Chemical Biology 20, 1340-1350. PMID: 24738946
  8. Benjamin DI, Cozzo A, Ji X, Roberts LS, Louie SM, Luo K, Nomura DK. (2013) The ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids that fuel cancer pathogenicity. Proceedings of the National Academy of Sciences, USA 110, 14912-14917. PMID: 23980144
  9. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng S-W, Cravatt BF. (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49-61. PMID: 20079333

Discovering new toxicological mechanisms of environmental and pharmaceutical chemicals using chemoproteomic platforms

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 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. Publications on this topic can be found below:

  1. Counihan JL, Duckering M, Dalvie E, Ku W-m, Bateman LA, Fisher KJ, Nomura DK. (2017) Mapping proteome-wide reactivity of the widely used herbicide acetochlor in mice. ACS Chemical Biology 12, 635-642. PMID 28094496
  2. Ford B, Bateman LA, Gutierrez-Palominos L, Park R, Nomura DK. (2017) Mapping proteome-wide targets of glyphosate in mice. Cell Chemical Biology 24, 133-140. PMID 28132892
  3. Counihan JC, Ford B, Nomura DK. (2016) Mapping Proteome-Wide Interactions of Reactive Chemicals using Chemoproteomic Platforms. Current Opinions in Chemical Biology 30, 68-76. PMID 26647369
  4. Medina-Cleghorn D, Bateman LA, Ford B, Heslin A, Fisher KJ, Dalvie ED, Nomura DK. (2015) Mapping proteome-wide targets of environmental chemicals using reactivity-based chemoproteomic platforms. Chemistry and Biology 22, 1394-1405. PMID26496688
  5. Medina-Cleghorn D, Heslin A, Morris PJ, Mulvihill MM, Nomura DK. (2014) Multidimensional profiling platforms reveal metabolic dysregulation caused by organophosphorus pesticides. ACS Chemical Biology 9, 423-432. PMID: 24205821
  6. Nomura DK#, Casida JE#. (2011) Activity-based protein profiling of organophosphorus and thiocarbamate pesticides reveals multiple secondary targets in the mammalian nervous system. Journal of Agricultural and Food Chemistry 59, 2808-2815. PMID: 21341672 (# co-corresponding author)
  7. Nomura DK, Blankman JL, Simon GM, Fujioka K, Issa RS, Ward AM, Cravatt BF, Casida JE. (2008) Activation of the endocannabinoid system by organophosphorus nerve agents. Nature Chemical Biology 4, 373-378. PMID: 18438404

 

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