Our Research

Research Overview

The Nomura Research Group is focused on reimagining druggability using chemoproteomic platforms to develop 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 affect protein function. Our research group addresses this challenge by applying and advancing chemoproteomic platforms to discover and therapeutically target undruggable proteins, pathways, and diseases.

Major Research Directions

  1. Advancing chemoproteomics-enabled covalent ligand discovery platforms to therapeutically target undruggable proteins, pathways, and diseases
  2. Discovering and exploiting unique druggable modalities accessed by natural products
  3. Using chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation and discover new drug discovery technologies
  4. Mapping important metabolic nodes in disease using chemoproteomic and metabolomic platforms
  5. Using chemoproteomic platforms to map proteome-wide toxicological or therapeutic targets of environmental and pharmaceutical chemicals

Chemo-Proteomics

Covalent Ligands to Access Druggable Hotspots

Druggable Hotspots Accessed 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 activity-based protein profiling (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. Chung CY-S*, Shin HR*, Berdan CA, Ford B, Ward CC, Olzmann JA, Zoncu R#, Nomura DK# (2019) Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition. Nature Chemical Biology doi: 10.1037/s41589-019-0308-4. PMID 31285595 (*co-first authorship; #co-corresponding authorship) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper) PDF
  2. Ward CC, Kleinman JI, Brittain SM, Lee PS, Chung CYS, Kim K, Petri Y, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Nomura DK (2019) Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chemical Biology doi: 10.1021/acschembio.8b01083. PMID 31059647 (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper) PDF
  3. Spradlin JN, Hu X, Ward CC, Brittain SM, Jones MD, Ou L, To M, Proudfoot A, Ornelas E, Woldegiorgis M, Olzmann JA, Bussiere DE, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Maimone TJ*, Nomura DK* (2019) Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nature Chemical Biology doi: 10.1038/s41589-019-0304-8. PMID 31209351 (*co-corresponding authors) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper) PDF
  4. Counihan JL*, Wiggenhorn A*, Anderson KE, Nomura DK. (2018) Chemoproteomics-enabled covalent ligand screening reveals ALDH3A1 as a lung cancer target. ACS Chemical Biology 13, 1970-1977. PMID 30004670 (*co-first authors) PDF
  5. 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) PDF
  6. 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 PDF
  7. Bateman LA#, Nguyen TB#, Roberts AM#, Miyamoto DK, Ku W-M, Huffman TR, Petri Y, 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) PDF
  8. 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 PDF
  9. 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 PDF
  10. Ward CC, Kleinman J, Nomura DK. (2017) NHS-esters as versatile reactivity-based probes for mapping proteome-wide ligandable hotspots. ACS Chemical Biology 12, 1478-1483. PMID 28445029 PDF
  11. 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 23, 1-12. PMID 27185638 PDF
  12. Kohnz RA, Mulvihill MM, Chang JW, Hsu K-L, Sorrentino A, Cravatt BF, Bandyopadhyay S, Goga A, Nomura DK. (2015) Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer. ACS Chemical Biology 10, 1624-1630 PMID: 25945974 PDF
  13. Hunerdosse D, Morris PJ, Miyamoto DK, Fisher KJ, Bateman LA, Ghazaleh J, Zhong S, Nomura DK. (2014) Chemical Genetics Screening Reveals KIAA1363 as a Cytokine-Lowering Target. ACS Chemical Biology. Doi: 10.1021/cb500717g. PMID: 25343321. PDF
  14. 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 PDF
  15. 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) PDF
  16. 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 PDF
  17. 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 PDF
  18. Nomura DK, Leung D, Chiang KP, Quistad GB, Cravatt BF, Casida JE. (2005) A Brain Detoxifying Enzyme for Organophosphorus Nerve Poisons. Proceedings of the National Academy of Sciences, USA 102, 6195-6200. PMID: 15840715 PDF

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. Spradlin JN, Hu X, Ward CC, Brittain SM, Jones MD, Ou L, To M, Proudfoot A, Ornelas E, Woldegiorgis M, Olzmann JA, Bussiere DE, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Maimone TJ*, Nomura DK* (2019) Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nature Chemical Biology doi: 10.1038/s41589-019-0304-8. PMID 31209351 (*co-corresponding authors) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper) PDF
  2. Berdan CA, Ho R, Lehtola HS, To M, Hu X, Huffman TR, Petri Y, Altobelli CR, Demeulenaere SG, Olzmann JA, Maimone TJ*, Nomura DK* (2019) Parthenolide covalently targets and inhibits focal adhesion kinase in breast cancer cells. Cell Chemical Biology pii: S2451-9456(19)30112-6. Doi: 10/1016/j.chembiol.2019.03.016. PMID 31080076 (*co-corresponding authorship) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper) PDF
  3. 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) PDF
  4. 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 PDF

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.

  1. Spradlin JN, Hu X, Ward CC, Brittain SM, Jones MD, Ou L, To M, Proudfoot A, Ornelas E, Woldegiorgis M, Olzmann JA, Bussiere DE, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Maimone TJ*, Nomura DK* (2019) Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nature Chemical Biology doi: 10.1038/s41589-019-0304-8. PMID 31209351 (*co-corresponding authors) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper) PDF
  2. Ward CC, Kleinman JI, Brittain SM, Lee PS, Chung CYS, Kim K, Petri Y, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Nomura DK (2019) Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chemical Biology doi: 10.1021/acschembio.8b01083. PMID 31059647 (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper) PDF

Mapping important metabolic nodes in disease using chemoproteomic and metabolomic platforms

Since the discoveries of Otto Warburg in the 1920’s showing that cancer cells are addicted to glucose metabolism, we have known that cancer cells possess fundamentally altered metabolism that drives nearly every aspect of their pathogenicity. Thus, targeting metabolic drivers of cancer promises to yield new cancer therapies. While several promising metabolic targets have been identified, most metabolic targets stem primarily from central carbon metabolism and likely represent just the tip of the iceberg in terms of metabolic enzyme targets that can be exploited for cancer therapy. We believe that advancing chemical technologies to rapidly and more comprehensively identify metabolic drivers of cancer will enable the discovery of novel and targeted cancer therapies. Another major research focus has been to apply innovative chemoproteomic and metabolomic platforms to couple the rapid discovery, characterization, and pharmacological targeting of novel metabolic cancer targets.

  1. Counihan JL*, Wiggenhorn A*, Anderson KE, Nomura DK. (2018) Chemoproteomics-enabled covalent ligand screening reveals ALDH3A1 as a lung cancer target. ACS Chemical Biology 13, 1970-1977. PMID 30004670 (*co-first authors) PDF
  2. Counihan JL, Grossman EA, Nomura DK. (2018) Cancer metabolism: current understanding and therapies. Chemical Reviews 118, 6893-6923. PMID 29939018 PDF
  3. 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 PDF
  4. 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 PDF
  5. 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 PDF
  6. 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) PDF
  7. 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 23, 1-12. PMID 27185638 PDF
  8. Piano V#, Benjamin DI#, Valente S, Nenci S, Mai A, Aliverti A, Nomura DK*, Mattevi A*. (2015) Discovery of inhibitors for the ether lipid-generating enzyme AGPS as anti-cancer agents. ACS Chemical Biology doi: 10.1021/acschembio.5b00466. PMID 26322624 (# equal contribution; * co-corresponding authors). PDF
  9. Kohnz RA, Mulvihill MM, Chang JW, Hsu K-L, Sorrentino A, Cravatt BF, Bandyopadhyay S, Goga A, Nomura DK. (2015) Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer. ACS Chemical Biology 10, 1624-1630 PMID: 25945974 PDF
  10. 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 PDF
  11. Hunerdosse D, Morris PJ, Miyamoto DK, Fisher KJ, Bateman LA, Ghazaleh J, Zhong S, Nomura DK. (2014) Chemical Genetics Screening Reveals KIAA1363 as a Cytokine-Lowering Target. ACS Chemical Biology. Doi: 10.1021/cb500717g. PMID: 25343321. PDF
  12. 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 PDF
  13. 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) INPP1 Promotes Cancer Aggressiveness by Linking Inositol Phosphate Recycling to Glycolytic and Lipid Metabolism. ACS Chemical Biology 20, 1340-1350. PMID: 24738946 PDF
  14. 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 PDF
  15. Louie SM*, Roberts LS*, Mulvihill MM, Luo K, Nomura DK. (2013) Cancer cells incorporate and remodel exogenous fatty acids into structural and oncogenic signaling lipids. Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids 1831, 1566-1572. PMID: 23872477 (* authors contributed equally to the work) PDF
  16. Cao Z, Mulvihill MM, Mukhopadhyay P, Xu H, Erdelyi K, Hao E, Holovac E, Hasko G, Cravatt BF, Nomura DK#, Pal Pacher#. (2013) Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology 144, 808-817. PMID: 23295443 (# co-corresponding authors) PDF
  17. Piro JR, Benjamin DI, Duerr JM, Pi YQ, Gonzales C, Schwartz JW, Nomura DK#, Samad TA#. (2012) A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer’s Disease. Cell Reports 1, 617-623. PMID: 22813736 (# co-corresponding author) PDF
  18. 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) PDF
  19. Nomura DK#, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, Hoover HH, Cravatt BF#. (2011) Monoacylglycerol lipase exerts bidirectional control over endocannabinoid and fatty acid pathways to support prostate cancer pathogenesis. Chemistry & Biology 18, 848-856. PMID: 21802006 (# co-corresponding author) PDF
  20. Nomura DK, Dix MM, Cravatt BF. (2010) Chemoproteomic Approaches for Biochemical Pathway Discovery in Cancer. Nature Reviews Cancer 10, 630-638. PMID: 20703252 PDF
  21. 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 PDF
  22. Ruby M*, Nomura DK*, Hudak CS, Mangravite LM, Chiu S, Casida JE, Krauss RM. (2008) Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins. Proceedings of the National Academy of Sciences, USA 105, 14561-14566. PMID: 18794527 (* co-first author) PDF
  23. Nomura DK, Ward AM, Hudak CS, Burston JJ, Issa RS, Fisher KJ, Abood ME, Wiley JL, Lichtman A, Casida JE. (2008) Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels. Bioorganic Medicinal Chemistry Letters 18, 5875-5878. PMID: 18752948 PDF
  24. 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 PDF
  25. Nomura DK, Fujioka K, Issa RS, Ward AM, Cravatt BF, Casida JE. (2008) Dual Roles of Brain Serine Hydrolase KIAA1363 in Ether Lipid Metabolism and Organophosphate Detoxification. Toxicology and Applied Pharmacology 228, 42-482. PMID: 18154358 PDF

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 PDF
  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 PDF
  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 PDF
  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 & Biology 22, 1394-1405. PMID 26496688 PDF
  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 PDF
  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) PDF
  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 PDF
  8. Casida JE, Nomura DK, Vose SC, Fujioka K. (2008) Organophosphate-Sensitive Lipases Modulate Brain Lysophospholipids, Ether Lipids and Endocannabinoids. Chemico-Biological Interactions 175, 355-64. PMID: 18495101
  9. Nomura DK, Fujioka K, Issa RS, Ward AM, Cravatt BF, Casida JE. (2008) Dual Roles of Brain Serine Hydrolase KIAA1363 in Ether Lipid Metabolism and Organophosphate Detoxification. Toxicology and Applied Pharmacology 228, 42-482. PMID: 18154358 PDF
  10. Nomura DK, Durkin KA, Chiang KP, Quistad GB, Cravatt BF, Casida JE. (2006) Serine Hydrolase KIAA1363: Toxicological and Structural Features with Emphasis on Organophosphate Interactions. Chemical Research in Toxicology 19, 1142-1150. PMID: 16978018 PDF
  11. Nomura DK, Leung D, Chiang KP, Quistad GB, Cravatt BF, Casida JE. (2005) A Brain Detoxifying Enzyme for Organophosphorus Nerve Poisons. Proceedings of the National Academy of Sciences, USA 102, 6195-6200. PMID: 15840715 PDF

 

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