Our Research

Research Overview

The Nomura Research Group is focused on redefining druggability using chemoproteomic platforms to innovative transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “druggable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by applying and advancing chemoproteomic platforms to discover and pharmacologically target novel druggable hotspots for disease therapy.

Major Research Directions

  1. Chemoproteomics-enabled covalent ligand discovery platforms to map and pharmacologically target druggable hotspots to tackle the undruggable proteome
  2. Covalent ligand discovery against druggable hotspots targeted by natural products for disease therapy
  3. Chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation for drug discovery
  4. Using chemoproteomic platforms to map proteome-wide toxicological or therapeutic targets of environmental and pharmaceutical chemicals

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 redefining druggability using chemoproteomic platforms to innovative transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “druggable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by applying and advancing chemoproteomic platforms to discover and pharmacologically target unique and novel druggable hotspots for disease therapy. We currently have four major research directions. Our first major focus is on applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel druggable hotspots for undruggable protein targets and incurable diseases. Our second research area focuses on covalent ligand discovery against druggable hotspots targeted by therapeutic natural products using chemoproteomic platforms to discover new therapeutic targets and synthetically tractable therapies for complex human diseases. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation to target and degrade undruggable proteins. Our fourth research area focuses on using chemoproteomic platforms to map on and off-targets of environmental and pharmaceutical chemicals towards discovering new toxicological mechanisms. Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery.

Chemoproteomics-enabled covalent ligand discovery to drug the undruggable proteome

One of the biggest challenges in curing human diseases is that most, 90 %, of the proteome is considered “undruggable”—most proteins are devoid of known functional binding pockets or “druggable hotspots” that drugs can bind to modulate their functions for disease therapy. Developing new approaches to both discover binding pockets or “druggable hotspots” and to pharmacologically target these sites with small-molecules will radically expand our scope of the druggable proteome and lead to new disease cures. Multiple technologies have arisen to tackle the undruggable proteome. One major strategy is a chemoproteomic platform termed isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) that uses reactivity-based chemical probes to map proteome-wide reactive, functional, and druggable hotspots directly in complex proteomes. When used in a competitive manner, covalent ligands can be competed against reactivity-based probe binding to druggable hotspots to pharmacologically target undruggable proteins. A major focus of our lab is to couple the phenotypic or biochemical screening of covalent ligand libraries with chemoproteomic platforms to rapidly discover therapeutic small-molecule leads and druggable hotspots against undruggable protein targets and incurable diseases. Publications on this topic are 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. Cell Chemical Biology doi:10.1016/j.chembiol.2017.08.013. PMID 28919038 (*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 53, 7234-7237. 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
  6. 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
  7. 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
  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

Covalent ligand discovery against druggable hotspots targeted by anti-cancer natural products using chemoproteomic platforms

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 drugs. 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:

  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. Cell Chemical Biology doi:10.1016/j.chembiol.2017.08.013. PMID 28919038 (*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

Expanding the scope of the degradable proteome using chemoproteomic platforms

Another groundbreaking technology enabling drug discovery efforts against undruggable targets is termed targeted protein degradation that exploits cellular protein degradation machinery to selectively eliminate target proteins. Targeted protein degradation involves the utilization of bifunctional molecules called “degraders” with one end consisting of a small-molecule ligand that binds to the protein of interest linked to another end consisting of an E3 ligase recruiting small-molecule binding to an E3 ligase which in-turn ubiquitinates and proteosomally degrades the target. The promise of this strategy is that targeted protein degradation can be potentially used to target and degrade any protein target in the proteome, including the undruggable proteome. However, two major challenges exist in the application of this technology. First, undruggable targets by definition are likely not to possess ligands that bind to them. Second, while there are >500 different E3 ligases, there are only a few E3 ligase recruiters. To overcome the first challenge, our research group couples chemoproteomics-enabled covalent ligand discovery platforms with targeted protein degradation technologies to pharmacologically target and proteosomally degrade undruggable protein targets. To overcome the second challenge, our group has also been using chemoproteomics-enabled covalent ligand screening approaches to develop an arsenal of new E3 ligase recruiters  that can be coupled to linkers and protein-targeting ligands to enable degradation of protein targets.

 

Developing safer 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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