Daniel K. Nomura
Professor of Biochemistry, Biophysics and Structural Biology*Lab Homepage: http://www.nomuraresearchgroup.com/
*and of Chemistry and of Nutritional Sciences & Toxicology
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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 developing 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 developing 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. Collectively, we have identified >100,000 potential ligandable binding pockets across >20,000 proteins suggesting that we can develop small-molecule modulators against not just 10 % but rather the majority of the proteome. A major focus of our lab is to couple the phenotypic or biochemical screening of our covalent ligand libraries with our chemoproteomic platforms to rapidly discover therapeutic small-molecule leads and druggable hotspots against undruggable protein targets and incurable diseases.
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.
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.
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 24, 1368-1376. PMID 28919038 (*co-first authorship)
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)
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
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 12, 2522-2528. PMID 28892616
Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MT, Jedrychowski MP, Paolo J, Griffin PR, Nomura DK*, Spiegelman BM* (2016) PM20D1 secretion by thermogenic adipose cells regulates lipidated amino acid uncouplers of mitochondrial respiration. Cell 166, 424-435. PMID 27374330 (*co-corresponding authorship)
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
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
Nomura DK#, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, Ward AM, Hahn YK, Lichtman AH, Conti B, Cravatt BF#. (2011) Endocannabinoid hydrolysis generates brain eicosanoids that promote neuroinflammation. Science 334, 809-813. PMID: 22021672 (# co-corresponding author)
Last Updated 2018-02-23