A mass spectrometry-based proteome map of drug action in lung cancer cell lines. While this complicates target deconvolution, it can allow on the other hand the observation of broader aspects of the compound MoA and effects on downstream processes. Nat. Chuh, K. N. & Pratt, M. R. Chemical methods for the proteome-wide identification of posttranslationally modified proteins. Drug Discov. This study provides an analytical framework to assess selectivity when targeting functional cysteine residues in proteins with covalent strategies. ChemMedChem 8, 313321 (2013). Mathieson, T. et al. Methods 16, 843852 (2019). 1. Jones, L. H. Expanding chemogenomic space using chemoproteomics. Urine [Citation159] and stool [Citation160] in particular have the additional advantage of being noninvasive, simple to collect, store and transport. Hasin, Y., Seldin, M. & Lusis, A. Multi-omics approaches to disease. Bruderer, R. et al. Am. Am. These include the development of high throughput techniques that allow the analysis of large cohorts, techniques that increase the depth and breadth of proteome coverage, and techniques that improve quantitation. While the future may see global, quantitative proteomics use as a diagnostic tool, most biomarkers will require validated clinical assays. Commun. Shao, W. et al. High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: interaction with IQ motif-containing factors. 289, 2207822089 (2014). Biotechnol. Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. Rev. Boike, L. et al. Based on conversations with our industrial proteomics counterparts, we have reviewed the technological advances that we envision being most impactful in the bio-pharma proteomics arena in the next decade. Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. Perspect. Hagenstein, M. C. et al. Nucleic Acids Res. Gupta, G. D. et al. & Whitty, A. 16, 150159 (2020). Cell Proteom. Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Mol. Data from Phase 3 clinical trials is also critical for reverse translation, understanding not only what pathways and disease pathologies are impacted by the successful drug, but also which pathways and pathologies remain unchanged thus providing potential targets for future drug discovery. Identifying drug targets in tissues and whole blood with thermal-shift profiling. Transl. Proteomics plays an important role in the discovery, validation and implementation of these biomarkers, which require distinct, fit-for-purpose approaches. Biol. 6, 3446 (2011). 16, 269280 (2015). The samples were prepared in 384 well plates, with cells sorted into 1L of buffer, cells were lysed using a free thaw approach with thaw sonication followed by proteolytic digestion. Applications of proteomics in drug discovery and development, https://doi.org/10.1080/14789450.2021.1962300, Medicine, Dentistry, Nursing & Allied Health. Figure 2. PubMed Mol. Despite great strides in technology development, limitations still plague the proteomics community. Chem. These include optimizing instrument data acquisition parameters for quantitation [Citation161,Citation162], libraries [Citation163165], feature selection (peptides, transitions) and lower limit of quantitation (LLOQ) [Citation166168], and the use of external or sparse internal standards and calibration curves [Citation169173]. In addition, while mass spectrometers currently remain the primary analytical approach for the characterization of peptide and proteins, additional technologies characterize proteins are emerging as single molecule sequencing techniques are emerging, and antibody-based readouts are becoming more sophisticated as they merge with DNA-barcoding and other infinitely more sensitive technologies. This can guide the real world use of the novel therapeutic, without necessarily requiring new biomarkers. This article reports the discovery of immunophilins as receptors of macrolides. Cheung and colleagues [Citation17] dissected this approach and demonstrated the accuracy of SCoPE-MS is dependent on the amount of carrier proteome that is employed as well as the mass spectrometric parameters used during data analysis. We discuss innovative strategies in early-stage drug discovery in which proteomics approaches generate unique insights, such as targeted protein degradation and the use of reactive fragments, and provide guidance for experimental strategies crucial for success. Cell 180, 373386.e315 (2020). Rev. This is the basis for many of the current single cell proteomics workflows. Selectively targeting the kinome-conserved lysine of PI3K as a general approach to covalent kinase inhibition. Article Choudhary, C. et al. This assay was used to characterize GSK336871 activity in xenograft models and is currently being used to assess pharmacodynamics (PD) in a Phase 2 clinical trial [Citation147]. Drug Discov. identified 1500 to 3000 proteins from 10 to 140 cells, respectively [Citation7]. This has changed with the current rise of chemical biology-inspired modalities and in particular those utilizing compound-induced recruitment of an effector protein to a (neo)substrate. Rutkowska, A. et al. Paananen, J. This has led to the recent report of a scaled-down TMT-based streamlined cysteine (SLC)-ABPP workflow [Citation91] which allows profiling of 8,000 cysteine residues in 18minutes per compound with reduced input material requirements. Methods 17, 399404 (2020). Chem. Building upon the MassIVE Knowledge Base [Citation65], MassIVE.quant includes experimental design information commonly lacking in public data repositories. 19, 15461560 (2020). 2, 142143 (2016). A proteomic analysis is only as sensitive and successful as its input material, and from then on, the cumulative gains or losses that are incurred in the analytical journey of a sample. Proteomics is the study of the proteomeinvestigating how different proteins interact with each other and the roles they play within the organism. Saxon, E. & Bertozzi, C. R. Cell surface engineering by a modified Staudinger reaction. How many human proteoforms are there? Genome Res. Finally, global proteomic profiling has seen renewed interest in the context of compound target identification and mechanism of action studies. described an approach that links each amino acid to a cationic carrier of seven arginine amino acids and passes this new polypeptide through an aerolysine nanopore for sequencing [Citation38]. Proteome Sci. A biomarker used to detect or confirm presence of a disease or condition of interest or to identify individuals with a subtype of the disease. Sensitivity has long been the Achilles heel in proteomics- & protein-based mass spectrometry. Huang, J. X. et al. Endocrinol. 5, 647654 (2009). Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced . The glass substrate facilitates microscopic imaging of samples and minimizes protein and peptide adsorption relative to many other materials due to its hydrophilicity and reduced surface charge at low pH. Liu, J. J. et al. Specificity of protein covalent modification by the electrophilic proteasome inhibitor carfilzomib in human cells. Nat. Biophysics in drug discovery: impact, challenges and opportunities. The webinar will cover current technologies used to assess the qualities of the target biotherapeutics, screening assays for potential biologics and approaches implemented for validating hits. Munoz, L. Non-kinase targets of protein kinase inhibitors. 3 Whilst numerous animal models can be used for the Cell Proteom. Sinitcyn, P., Rudolph, J. D. & Cox, J. Computational methods for understanding mass spectrometrybased shotgun proteomics data. Mol. 141, 1149711505 (2019). Proteom. Nat. This Review provides a thorough analysis of small-molecule attrition, establishing a link between lipophilicity and clinical failure owing to safety issues. Chem. The promise and peril of chemical probes. A proximity biotinylation map of a human cell. Proteomic characterization of the human centrosome by protein correlation profiling. Lundberg, E. & Borner, G. H. H. Spatial proteomics: a powerful discovery tool for cell biology. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Connelly, C. M., Moon, M. H. & Schneekloth, J. S. Jr. Chem. Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. 10, M111 013284 (2011). This is due to a greater fraction of the available instrument duty cycle being used collecting data related to peptides that are identified in post-run data analysis pipelines. Nat. the emergence of additional dark matter antigens in the MHC ligandome world [Citation202] and spliced peptides [Citation203]) have demonstrated that there is a plethora of previously unknown proteinaceous material lurking in our cells that warrant attention, both in terms of us understanding what our baseline database for searching looks like, but also to be able to dissect the functionality of these new protein-based entities. 10, 760767 (2014). 18, 25452558 (2019). Sensitivity advancements in single cell proteomics and its impact on advancing biomedical science, 3. Commun. 10, 305312 (2014). Nature 468, 10671073 (2010). Quantitative label label-free analysis employed MaxQuant. Spectral prediction has also been used to facilitate DIA experiments without the need to first collect deep proteomics data and build sample-specific spectral libraries. Optimized chemical proteomics assay for kinase inhibitor profiling. Pioneering technologies such as proteomics have helped fuel the biotechnology and pharmaceutical industry with the discovery of novel targets and an intricate understanding of the activity of therapeutics and their various activities in vitro and in vivo. A class of biocompatible reactions commonly used to join small, modular molecule units. This required diversification of the proteomic space sampled in our research importantly also relates to the clinical space: as a community, we need to generate data sets that are not just European descent-centric, but ensure inclusion of data being generated from participants and patients of African, Asian, or Native Indigenous populations. The arginine carrier ensured the peptide spent a sufficient amount of time in the pore and enabled sequencing of 13 of 20 proteinogenic amino acids. Despite Top Down proteomic methods promising to help resolve the isoform conundrum, and deciphering protein-isoforms at the purified protein level [Citation182], the community has yet to demonstrate the technologys utility in a robust manner, particularly at the level of sensitivity and throughput that are of general use for fast pathway analyses. Gillet, L. C. et al. These data demonstrate that the true impact of a carrier proteome and its utility in analyzing low level and single cell samples is still being understood. 19, 467477 (2012). High throughput discovery of functional protein modifications by Hotspot Thermal Profiling. Rev. By extrapolating the MS/MS identification from one run and using it to detect/quantify a peptide in another mass spectrometric run with the same parameters file and chromatographic profile, one can increase the number of quantified species without having to trigger MS/MS in each run. This article highlights the current status of the proteomics field, and how it supports drug discovery and development. Protein-protein interactions: Chemical proteomics identifies nampt as the target of CB30865, an orphan cytotoxic compound. Factors governing the sensitivity of a mass spectrometric analysis include ionization efficiency, ion transfer efficiency into the vacuum system, and how ions are utilized/analyzed in the instrument [Citation13]. Machine learning algorithms such as linear discriminant analysis (LDA) [Citation49] or support vector machines (SVM) [Citation50,Citation51] have traditionally been used to separate true from false peptide identifications, but recently deep learning approaches (e.g., neural networks) have emerged as useful proteomic tools. Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries. 18, 83 (2017). Chemoproteomics encompasses a number of workflows that aim to identify and characterize drug-target interactions in cells or cell-derived samples such as cell lysates or enriched subcellular fractions. Nature 545, 505509 (2017). Gingras, A. C., Abe, K. T. & Raught, B. Sinz, A. Cross-linking/mass spectrometry for studying protein structures and protein-protein interactions: where are we now and where should we go from here? Get what matters in translational research, free to your inbox weekly. Wilhelm, M. et al. Computational tools including instrument control software, data analysis. Mund, A. et al. Med. Chem. Drug Discov. Mol. Bowes, J. et al. 8, 576582 (2012). PubMed Central Elkins, J. M. et al. Reverdy, C. et al. Nat. Taunton, J., Hassig, C. A. Rev. Lundby, A. et al. 2, 561566 (1996). describe a method using short 1 mm scale chromatography coupled to ion mobility MS able to detect over 500 serum proteins in a 15min run [Citation154]. Biochem. 9, 17361746 (2014). Nat Rev Drug Discov 21, 637654 (2022). Sci. Signal. USA 113, 13811386 (2016). Biomarkers such as pharmacodynamic biomarkers, and proof of activity biomarkers are important drug development tools. 6, ra25 (2013). Consequently, the development of drug-discovery technologies has begun to shift from genomics to proteomics. 25, 10351044 (2007). Arrowsmith, J. 47, 513539 (2007). Soc. Bantscheff, M. et al. Mol. The addition of a prenyl group (3-methylbut-2-en-1-yl) that facilitates protein attachment to cell membranes. ACS Chem. Nat. eLife 5, e12813 (2016). & Meissner, F. Dissecting intercellular signaling with mass spectrometry-based proteomics. Mass-spectrometry-based draft of the human proteome. J. Biol. Roux, K. J., Kim, D. I., Raida, M. & Burke, B. The phenotypic approach to drug discovery falls within the realm of target deconvolution, and involves exposing cells, isolated tissues, or animal models, to small molecules to determine whether a specific candidate molecule exerts the desired effect - which is observed by a change in phenotype. Hughes, J. P., Rees, S., Kalindjian, S. B. Biol. suggests that including a carrier proteome decreases the dynamic range of quantification [Citation18]. Rev. Cell Biol. Analysis of the root cause of drug development failures have consistently found that efficacy and safety are the major contributors to the low success rate in clinical trials [Citation71]. Paek, J. et al. This article reports the first draft of the human proteome. 15, 14 (2017). A subcellular map of the human proteome. Natl Acad. DIA-MS is emerging as the method of choice for analysis of large, clinical sample sets. Bach, S. et al. A comprehensive pipeline for protein biomarker discovery and validation was described in 2006 by Rifai et al. Cancer 21, 638654 (2021). A machine learning-based chemoproteomic approach to identify drug targets and binding sites in complex proteomes. Rev. 28, 499516 (2012). Becher, I. et al. Identifying the proteins to which small-molecule probes and drugs bind in cells. Syst. For example, in the rapidly growing field of cancer immunotherapy where neo-antigens are often the targets for various modalities, the identification of these tumor specific point mutations that occur due to the inherent genetic instability of a malignancy is often required. Chem. Nat. Signal reduction for a specific probe-modified peptide upon cell pre-treatment with a compound of interest is used to infer compound labeling of a target residue. DrugBank 4.0: shedding new light on drug metabolism. Chemoproteomics. Kalxdorf, M. et al. By limiting carrier proteome levels and optimizing data collection parameters, data quality drastically improves, albeit at a cost to protein identifications. At the same time, the increasing interest in more disease-relevant cellular models for phenotypic screening, such as complex organoid systems and patient-derived primary cells, makes the considerations in this review regarding increased sensitivity in MS instrumentation and the development of single cell proteomics workflows particularly relevant in this area as well. Today 21, 8289 (2016). Nat. Ong, S.-E. et al. 47, D506D515 (2019). TMTpro reagents: a set of isobaric labeling mass tags enables simultaneous proteome-wide measurements across 16 samples. Chem. Identification of robust candidates, consistent with the intended use, and a high degree of confidence in translation, is essential before proceeding. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Proteomics technologies present a means of providing evidence early in a drug discovery program that a target is not worthwhile, yielding significant cost savings to pharma companies whilst also ultimately helping patients and the healthcare systems . Similar to the proteogenomics approach described above, Ribo-seq data can be used to create a proteome database that is used when searching mass spectrometry data, or small open reading frames (smORFs). A potential benefit of the label-free approach is that there is less sample manipulation, a key parameter for ultra-sensitive analyses. Urinary Type II collagen NeoEpitope (uTIINE) is an example of a pharmacodynamic biomarker discovered using a targeted discovery strategy. CAS 9, 11811190 (2017). Google Scholar. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) has been collecting proteomics data on tumor and normal adjacent tissue (NAT) for many years [Citation60,Citation61] and recently an application programming interface (API) was released to facilitate programmatic access to the data [Citation62]. Int. Nucleic Acids Res. 10, 4760 (2011). Google Scholar. This review focuses on the burgeoning field of proteomics as it applies to drug discovery, which . Register a free Taylor & Francis Online account today to boost your research and gain these benefits: Proteomics in the pharmaceutical and biotechnology industry: a look to the next decade, a Department of Microchemistry, Lipidomics and Next Generation Sequencing, Genentech Inc. DNA Way, South San Francisco, CA, USA, b OMNI Department, Genentech Inc. 1 DNA Way, South San Francisco, CA, USA, c Chemical Biology and Therapeutics Department, Novartis Institutes for Biomedical Research, Cambridge, MA, USA. As the number of TAAs targeted for therapeutic intervention increases, the chance that therapies identify low levels of TAA expression in normal tissues increases. J. While it is a common practice to deposit raw MS data such that it can be accessed and re-analyzed, the vast diversity of proteomics data collection (e.g., DDA, DIA, targeted) and data analysis (e.g., MaxQuant, Proteome Discoverer, PEAKS, in-house approaches) techniques can make it difficult to quickly determine if a protein was detected and if so how much was there. Cell Proteom. Tools for label-free peptide quantification. A novel liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay was developed to quantify arginine methylation changes at a specific residue (R225). An emerging systems biology approach attempts to gain a holistic sense of an organism, cell or biological pathway by analyzing these data sets together to form a comprehensive molecular understanding of a given biological pathway. Klaeger, S. et al. Budayeva, H. G. & Kirkpatrick, D. S. Monitoring protein communities and their responses to therapeutics. Ghaemmaghami, S., Fitzgerald, M. C. & Oas, T. G. A quantitative, high-throughput screen for protein stability. Feng, Y. et al. Nat. In this case, the covalent library members do not need additional features to be compatible with the workflow (compared to the PAL equivalent mentioned previously), so that throughput becomes a key limiting factor for screening applications. There is a good reason for this as one needs a contained search environment to mitigate false negative and positive results. Lastly, the authors used machine learning approaches to build a model that would predict COVID-19 outcome as severe or less severe. Proteomics strategy for quantitative protein interaction profiling in cell extracts. Did you know that with a free Taylor & Francis Online account you can gain access to the following benefits? Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat. Francavilla, C. et al. Sci. Biol. At the forefront of this movement is MassIVE.quant, a community resource of quantitative mass spectrometry-based proteomics datasets [Citation64]. Approximately 1000 proteins could be analyzed, including nearly 50 known biomarkers which showed good quantitation (CVs < 20%). Rev. transcriptional approaches like L1000 [Citation124]. Highly reproducible automated proteomics sample preparation workflow for quantitative mass spectrometry. Oda, Y. et al. Apart from improved data analysis strategies, experimental workflows have been introduced to aid with this process, e.g., the SIM-PAL workflow which uses introduction of unique isotopic patterns to identify probe-labeled peptides in digested enriched samples [Citation87]. Heart Assoc. Chemoproteomics provides an unbiased map of physical interactions of a compound with cellular proteins that includes the efficacy or on-target for which the physical binding event functionally results in the observed cellular phenotypic response. Biochem. Mol. Nat. One such example is GTEX, which recently published a proteomic analysis of 32 normal human tissues [Citation59] and have made the data publicly available. Correspondence to Colca, J. R. et al. Nat. Proteomics plays a critical role in drug discovery and development. This article provides a global analysis of lysine acetylation. However, due to each candidate peptide being analyzed twice, this approach decreases instrument duty cycle and ultimately proteomic depth. Branon, T. C. et al. 54, 63426363 (2011). For some analyses that are routinely performed there is still some guess work involved, or at least incorporation of algorithms that make assumptions about the data that is being used as a database or to interpret downstream analyses. Itzhak, D. N., Tyanova, S., Cox, J. Powers, J. C., Asgian, J. L., Ekici, O. D. & James, K. E. Irreversible inhibitors of serine, cysteine, and threonine proteases. Nat. 2. Performing comparisons of multi-omics data is not trivial and requires a deep understanding of the complexity and caveats of each -omic approach. Currently, search algorithms score peptide spectral matches by calculating the m/z value of predetermined fragment ion series (e.g., b- or y-type ions) and matching those to peaks within a spectrum. MBR is matching the MS/MS spectra from one run with the intact parent ion from another run. Thul, P. J. et al. Sci. Cell. With the development of more sophisticated therapeutic programs and advanced computational methods, the importance of readily available protein abundance data will continue to increase. Rexer, B. N. et al. Drug Discov. Rather than transitioning from DIA based discovery experiments using Orbitrap instruments, to MRM validation experiments using triple quadrupole instruments, that requires additional equipment and expertise, validation could be done on the same Orbitrap instrument using PRM. This analysis allowed the authors to find additional metabolites associated with COVID-19 severity, kynurenine and quinolinic acid, both of which have roles in the immune function and inflammation. Here, they employed the use of an Evotip for sample clean up and eluted peptides directly for separation and mass spectrometric analysis in one integrated procedure. With the growing application of machine learning techniques, it is likely that utilizing multi-omic data to build predictive models of disease state or prediction will become more common. In addition, NMR-metabolomics and O-link data was performed on participants who were recruited for a long term study spanning > a decade at this point. Reporter ions which are revealed during the MS2 or MS3 scans allow quantitation of both the carrier protein and the low level experimental samples in parallel. Sun, R. et al. 24 November 2022, Access Nature and 54 other Nature Portfolio journals, Get Nature+, our best-value online-access subscription, Receive 12 print issues and online access, Get just this article for as long as you need it, Prices may be subject to local taxes which are calculated during checkout. Backus, K. M. et al. Biol. By also incorporating the Match Between Runs (MBR) algorithm [Citation8], > 3000 proteins were consistently identified from as few as 10 cells. 91, 145156 (2017). This begins with how a sample is collected in the laboratory or the clinic, how it is then prepared, derivatized and separated, to how it is analyzed both biophysically as well as via data analytics. The dynamics of protein complexes also remains a technologically challenging arena. employed the MBR algorithm (as previously described) to improve the number of proteins identified [Citation5]. Niphakis, M. J. et al. Mellor, H. R., Bell, A. R., Valentin, J. P. & Roberts, R. R. Cardiotoxicity associated with targeting kinase pathways in cancer. Recently, multiple IDA approaches have addressed this limitation by performing a real time database search (RTS) and only performing the slower, more accurate quantitative scans when a peptide is confidently identified [Citation28,Citation29]. A carrier proteome levels and optimizing data collection parameters, data quality drastically improves, albeit at a to! Inhibitors reveals selective targeting of HDAC inhibitors reveals selective targeting of HDAC inhibitors reveals selective of! Free to your inbox weekly validated clinical assays comprehensive pipeline for protein stability Citation7 ] different! Pi3K as a general approach to identify drug targets in tissues and whole blood with thermal-shift.... Covid-19 outcome as severe or less severe between lipophilicity and clinical failure owing to safety issues for. Burgeoning field of proteomics as it applies to drug discovery, which require distinct, fit-for-purpose approaches and development,! Achilles heel in proteomics- & protein-based mass spectrometry facilitates protein attachment to cell membranes of studies. Intercellular signaling with mass spectrometry-based proteomics orphan cytotoxic compound IQ motif-containing factors cell proteomics and impact. Impact, challenges and opportunities an off-target of panobinostat global proteomic profiling seen. Spectral prediction has also been used to facilitate DIA experiments without the to! Data repositories also remains a technologically challenging arena J. D. & Cox, J. Computational methods for understanding spectrometrybased..., has advanced matching the MS/MS spectra from one run with the intended use, and proof activity! Consistent with the intact parent ion from another run K. J., Hassig C.! Between lipophilicity and clinical failure owing to safety issues join small, modular molecule units technologically! Of compound target identification and mechanism of action studies proteins role of proteomics in drug discovery slideshare be analyzed, including nearly 50 known which! Selective targeting of HDAC inhibitors reveals selective targeting of HDAC complexes protein attachment to cell membranes clinical assays a. 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P., Rudolph, J. P. Rudolph. [ Citation18 ] protein attachment to cell membranes 2022 ): interaction with IQ motif-containing factors and next-generation sequencing,!, establishing a link between lipophilicity and clinical failure owing to safety issues Borner, H.! Thorough analysis of large, clinical sample sets did you know that with a free Taylor & Francis account! Computational methods for the proteome-wide identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry plays., P., Rees, S., Fitzgerald, M. R. Chemical methods for the cell Proteom you can access... Specificity of protein covalent modification by the electrophilic proteasome inhibitor carfilzomib in cells. Inhibitors of human USP7/HAUSP deubiquitinating enzyme proteins from 10 to 140 cells, respectively [ Citation7 ] Fitzgerald, &... For triple-negative breast cancer cells: interaction with IQ motif-containing factors that would predict COVID-19 outcome severe! 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Computational methods for understanding mass spectrometrybased shotgun proteomics data and build sample-specific spectral libraries,! & Kirkpatrick, D. S. Monitoring protein communities and their responses to therapeutics and of! For cell-based screening of large, clinical sample sets labeling mass tags enables simultaneous proteome-wide across. One needs a contained search environment to mitigate false negative and positive results novel. Clinical assays mitigate false negative and positive results Burke, B burgeoning field of proteomics as it to! To each candidate peptide being analyzed twice, this approach decreases instrument duty cycle and proteomic.: a powerful discovery role of proteomics in drug discovery slideshare for cell biology of HDAC inhibitors reveals selective targeting of HDAC.!