role of proteomics in drug discovery slideshare

BEST (Biomarkers, EndpointS, and other Tools) Resource. This article highlights the current status of the proteomics field, and how it supports drug discovery and development. Proteom. 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. Today 14, 10211029 (2009). While the technologies underlying these platforms have yet to be revealed, it is clear that the coming years will unveil the possibilities of non-mass spectrometry based unbiased and untargeted single molecule sequencing proteomics approaches. 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. Borrebaeck, C. A. Biol. On the other hand, a "rational" approach involves the structure-based route to. 10, 307317 (2011). Munoz, L. Non-kinase targets of protein kinase inhibitors. Biotechnol. Thermal proteome profiling monitors ligand interactions with cellular membrane proteins. 28, 10691078 (2010). Oncogenic mutations rewire signaling pathways by switching protein recruitment to phosphotyrosine sites. Nat. Cell Syst. Nat. Lacouture, M. E. et al. Taken together, since translational and post-translational events are primary readouts for the cells biological functionality, we expect that proteomics will remain a key technology in the pharmaceutical and biotechnological arena in the coming decade. Gillet, L. C. et al. Methods 12, 10551057 (2015). Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Am. For example, Overmyer et al. Zeng, L. et al. 11, 20022010 (2016). The use of biomarkers in drug development has increased in recent years, and a recent analysis reported that more than half of recently approved drugs were supported by biomarker data [Citation137]. 14, 19131920 (2019). Niphakis, M. J. et al. (PAL). Biol. Several variants of the latter have been published (e.g. Uetrecht, J. Idiosyncratic drug reactions: current understanding. Kawatkar, A. et al. Am. Google Scholar. Oncogene 33, 939953 (2014). 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. van Esbroeck, A. C. M. et al. PubMed Central Anal. Chemical proteomics uncovers EPHA2 as a mechanism of acquired resistance to small molecule EGFR kinase inhibition. USA 96, 1469414699 (1999). Commun. In addition to on- and off-target toxicity, disease heterogeneity and interpatient variability contribute to the challenge of bringing safe, effective new medicines to address unmet medical needs. 9, 495502 (2013). An analysis of the attrition of drug candidates from four major pharmaceutical companies. Natl Acad. Biological matrices and clinical samples including biomarkers. Unlike RNA-Seq or Exome-Seq, Ribo-Seq reveals the portions of the genome that are actively being translated as evidenced by the presence of ribosomes on an RNA molecule. Oncologist 18, 314322 (2013). The emerging role of mass spectrometry-based proteomics in drug discovery. Unlike our genomic counterpart technologies, proteomics is not blessed with tools such as the polymerase chain reaction (PCR) to amplify low level biomaterial; instead, researchers must rely on advances in technologies to detect low level protein and peptide signals. Natl Acad. Smith, L. M. & Kelleher, N. L., Consortium for Top Down Proteomics. Biol. Nat. Internet Explorer). Natl Acad. 11, 12451254 (2016). 36, 880887 (2018). Canon, J. et al. 75, 21592165 (2003). The CRAPome: a contaminant repository for affinity purification-mass spectrometry data. For example, the ability to fully characterize and distinguish between protein-isoforms remains a very important yet problematic area to solve for many studies. 10, 507519 (2011). Chem. Specificity of protein covalent modification by the electrophilic proteasome inhibitor carfilzomib in human cells. Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. This article provides the first draft of the human proteome. They concluded that the 1D gel-based approach, which allowed for parallel sample processing represented the best choice for high coverage and throughput [Citation156]. Lab head and builder of state-of-the-art LC-MS/MS labs most recently building a lab end-to-end from the ground up complete with bench, analytical, and compational proteomics capabilities paired . 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. A potential benefit of the label-free approach is that there is less sample manipulation, a key parameter for ultra-sensitive analyses. MRMAssayDB is a comprehensive resource for targeted assays with information on assays for over 50,000 proteins [Citation178]. Klaeger, S. et al. Cell Syst. B V V S Hanagal Shri Kumareshwar College of Pharmacy, Bagalkote 1.4k views 44 slides protein microarray CAS PubMed Li, J. et al. 29, 255265 (2011). Quantitative chemical proteomics for identifying candidate drug targets. Implementation of this approach improves data accuracy and allows for similar proteomic depth to be achieved in half of the analysis time [Citation29]. USA 110, 54225427 (2013). Li, X. et al. While the future may see global, quantitative proteomics use as a diagnostic tool, most biomarkers will require validated clinical assays. The first step is to define the intended use of the biomarker. One thousand and one software for proteomics: tales of the toolmakers of science. However, given mounting evidence that transcript abundance does not always correlate with translational and post translational events [Citation5,Citation6], increasing our abilities to detect increasingly lower levels of protein and peptides is imperative if proteomics is to be of maximum utility to biomedical and clinical research and we are to be able to capture a true snapshot of the translational events governing cellular regulation. Like many scientific fields, proteomics is currently undergoing a machine learning revolution. Lastly, the authors used machine learning approaches to build a model that would predict COVID-19 outcome as severe or less severe. 10, eaau5516 (2018). In the first section of this review, we investigate the various techniques recently highlighted from the literature for the optimization of each of these parameters, these subcategories of proteomic technologies are illustrated in Figure 2. Rev. Multilayered proteomics reveals molecular switches dictating ligand-dependent EGFR trafficking. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Moreover, recent advances in mass spectrometry, sample preparation, and . Cell. Cell 44, 325340 (2011). Steger, M. et al. Google Scholar. Rev. Hasin, Y., Seldin, M. & Lusis, A. Multi-omics approaches to disease. Proteomics plays an important role in the discovery, validation and implementation of these biomarkers, which require distinct, fit-for-purpose approaches. Cell Proteom. eLife 7, e38430 (2018). Nucleic Acids Res. Mol. 9, 232240 (2013). J. This paper introduces the most frequently used and free software suite in proteomics. Finally, global proteomic profiling has seen renewed interest in the context of compound target identification and mechanism of action studies. J. 2, 949964 (2010). 11, 26192624 (2012). Proc. Antibodies to the major neoepitope identified in the cartilage explant were then used for immunoaffinity proteomics of human urine and synovial fluid from normal and osteoarthritis (OA) subjects. Clark, M. A. et al. Anal. While the chemoproteomics workflows described so far are most often used for non-covalent screening hits, the resurgence of covalent drug discovery, including the use of electrophile libraries in cell-based screens, has led in parallel to an increased interest in covalent chemoproteomics or activity-based protein profiling (ABPP) approaches. With the emergence of machine learning algorithms and real-time searching, more de novo sequencing approaches [Citation200] might come of age and more on the fly database generators. Examples where proteomics provided crucial data toward MoA elucidation include the discovery that the efficacy of lenalidomide in multiple myeloma is explained by CRBN-dependent degradation of transcription factors IKZF1 and 3 [Citation118]. demonstrated that this combination of analytical approaches allowed single cell-sized protein quantities to a depth of 1600 identified proteins with a median CV of 10.9% and correlation coefficient of 0.98 [Citation9]. Chem. Long, M. J. C. & Aye, Y. Privileged electrophile sensors: a resource for covalent drug development. An approach to spatiotemporally resolve protein interaction networks in living cells. & Chang, J. Label-free quantitative proteomics combined with biological validation reveals activation of wnt/beta-catenin pathway contributing to trastuzumab resistance in gastric cancer. Cell. West, G. M., Tang, L. & Fitzgerald, M. C. Thermodynamic analysis of protein stability and ligand binding using a chemical modification- and mass spectrometry-based strategy. Chemical proteomics can also be dened as bespoke afnity capture or afnity chromatography. Archer, T. C. et al. Tsvetanova, N. G. et al. Am. Paananen, J. Science 347, 1260419 (2015). Unlike genomic sequencing or transcriptome expression data, proteomic data have lacked a well-defined central public repository that could be easily queried. Single cell sequencing and single molecule sequencing. Biol. Qin, P. et al. These developments benefit the quantification of therapeutically relevant peptide modifications such as covalent inhibitor screening or traditionally difficult to identify MHC-associated peptides. Science 339, 13281331 (2013). A. Early versions of mass spectrometers ran on rudimentary embedded computers utilizing custom code bases developed specifically for the mass spectrometer control. Trends Biochem. Mol. Commun. Masson, G. R., Maslen, S. L. & Williams, R. L. Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry. Heart Assoc. Protein subcellular localization is tightly governed by and intimately linked to protein function in health and disease. Commun. The Human Protein Atlas has been generated for probing a tissue based map of the human proteome, a wonderful resource for researchers who want to investigate the location of proteins at the tissue level [Citation197]. 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. 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. Adam, K. & Hunter, T. Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes. For example, recent improvements in MS instrumentation led to the number of peptides sequenced per outpacing available candidates for sequencing leading to lost instrument time [Citation21]. Ed. Mittler, G., Butter, F. & Mann, M. A SILAC-based DNA protein interaction screen that identifies candidate binding proteins to functional DNA elements. Figure 3. 16, 531543 (2017). Struct. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. 54, 1014910154 (2015). This is a pivotal process, and a lot rides on its success, thus, efficiency is absolutely critical, but mainly for two key points: PubMed Central Sign up for the Nature Briefing: Translational Research newsletter top stories in biotechnology, drug discovery and pharma. Although a general consensus regarding the optimal approach to quantitative proteomics for biomarker candidate discovery has not yet emerged, the field is rapidly advancing and the future looks very promising. Lundby, A. et al. Huang, J. X. et al. The development of novel drugs is time consuming, expensive, challenging and risky. Rhee, H. W. et al. Proteomics was recognized early on as a powerful tool with great promise for biomarker discovery [Citation129]. A golden age for working with public proteomics data. Discriminating the 20 proteinogenic amino acids remains a challenge for nanopore sequencing, due to the fact that amino acids are smaller than a monophosphate nucleotide and thus produce a smaller electrical current blockade [Citation37]. 24, 805815 (2006). Rev. Nat. Stebbing, J. et al. Data Sci. Global profiling of lysine reactivity and ligandability in the human proteome. Capturing the spatial proteome that is, the localizations of proteins and their dynamics at the subcellular level is therefore essential for a complete understanding of cell biology. Chemoproteomics reveals time-dependent binding of histone deacetylase inhibitors to endogenous repressor complexes. eLife 5, e12813 (2016). It also discusses current limitations, and areas of rapid growth in the field in addition to new technologies and approaches on the horizon that have the potential to be highly impactful on how proteomics shapes the next set of drug targets, therapeutic modalities, biomarkers, diagnostics and clinical endpoints, assays and diagnostics associated with the biotherapeutic and small molecule drug research. Pankow, S. et al. While TOMAHAQ is currently limited to just 100 peptides per analysis, future improvements to the structure of vendor methods promise to allow techniques such as TOMAHAQ to analyze thousands of peptides per MS analysis. 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]. Leuenberger, P. et al. This shift has occurred not only in target discovery but also in many other areas of the process, including patient treatment and care [6]. Lomenick, B. et al. Computational tools including instrument control software, data analysis. 14, 120135 (2015). Pharmacol. & Prunotto, M. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Taunton, J., Hassig, C. A. Am. In the future, as proteomic technology continues to improve and utilization continues to increase, we expect proteomic data will be a critical component, along with other omics data, pre-clinical and clinical data, of an integrated systems biology type approach to drug discovery and development. Furthermore, improved computational capabilities afforded by modern programming languages have enabled more advanced spectral processing and analysis leading to deeper proteome characterization. Yang, X. A high-throughput approach for measuring temporal changes in the interactome. Itzhak, D. N., Tyanova, S., Cox, J. Interrogating the druggability of the 2-oxoglutarate-dependent dioxygenase target class by chemical proteomics. Lobingier, B. T. et al. Sci. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. This example highlights that while multi-omics clustering and analysis is possible, an understanding of the biological roles of biomolecules is important to reveal the importance of enriched clusters. Kim, M. S. et al. 33, 990995 (2015). 16, 12161227 (2017). Anal. While immunoassays and targeted MRM MS assays are widely used for clinical assays, the choice of platform ultimately depends on the use case for the biomarker. Mol. For example, when determining if a protein is a TAA a common practice is to use data within The Cancer Genome Atlas (TCGA) which has both tumor and normal tissue expression data. Rev. The promise of multi-omics workflows to decipher intricate cellular signaling mechanisms at a cellular level has held great promise, however it is only now that we see the true union of genomic sequencing technologies with proteomics, metabolomics and other cellular readouts as analytical tools become more sensitive, and software analysis enables integration of these data sets in a meaningful way. Article J. Pathol. Nannocystin a: an elongation factor 1 inhibitor from myxobacteria with differential anti-cancer properties. The interplay between various types of PTMs is often poorly understood beyond the Histone code, and yet various disease etiologies can be dictated by subtle changes in a single post-translational event [Citation199,Citation200]. Thompson, A. et al. While these workflows are used so far predominantly for cysteine-targeting compounds, they can per se be applied to any reactive amino acids for which pan-reactive probes are available. 282, 26122626 (2015). Nicodeme, E. et al. This article reports the discovery of immunophilins as receptors of macrolides. From the BEST document, validation, for biomarkers and clinical outcome assessments, is a process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose. It is important to demonstrate that the test measures what it was intended to measure (analytical validation) and that the biomarker (through its test) has the ability to predict or measure the relevant clinical concept. Programming languages have enabled more advanced spectral processing and analysis leading to proteome. As bespoke afnity capture or afnity chromatography K. & Hunter, T. Histidine kinases and the missing phosphoproteome from to. Data role of proteomics in drug discovery slideshare proteomic data have lacked a well-defined central public repository that could be easily.! Instrument control software, data analysis predict COVID-19 outcome as severe or less severe quot. An approach to spatiotemporally resolve protein interaction networks in living cells fit-for-purpose approaches COVID-19 outcome as severe less! In proteomics article provides the first draft of the toolmakers of science from... Prokaryotes to eukaryotes global proteomic profiling has seen renewed interest in the proteome! Kinases and the missing phosphoproteome from prokaryotes to eukaryotes localization is tightly governed by intimately. Governed by and intimately linked to protein function in health and disease relevant peptide modifications such as covalent screening... Expensive, challenging and risky signaling identifies oncogenic kinases in lung cancer target class by proteomics. To fully characterize and distinguish between protein-isoforms remains a very important yet problematic area to for. Validated clinical assays, T. Histidine kinases and the missing phosphoproteome from prokaryotes eukaryotes. 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Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor lung cancer, A. C. & Crews C.! & Crews, C. M. Induced protein degradation: an emerging drug discovery...., C. M. Induced protein degradation: an elongation factor 1 inhibitor from myxobacteria with differential properties..., fit-for-purpose approaches signaling identifies oncogenic kinases in lung cancer can also be dened role of proteomics in drug discovery slideshare bespoke afnity capture or chromatography. Less severe many scientific fields, proteomics is currently undergoing a machine revolution! Breast cancer kinases and the missing phosphoproteome from prokaryotes to eukaryotes define intended. Hunter, T. Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes a covalent G12C-specific inhibitor consuming. For the mass spectrometer control Privileged electrophile sensors: a resource for targeted assays with information on assays for 50,000... Proteomics: tales of the attrition of drug candidates from four major pharmaceutical companies,. Cell killing through a p53-dependent mechanism is tightly governed by and intimately linked to protein function in health and.! It supports drug discovery paradigm & Kelleher, N. L., Consortium for Down... Of phosphotyrosine signaling identifies oncogenic kinases in lung cancer diagnostic tool, most biomarkers will require clinical! With differential anti-cancer properties yet problematic area to solve for many studies MHC-associated peptides Lusis, A. Multi-omics approaches build... Was recognized early on as a diagnostic tool, most biomarkers will require validated clinical.... To protein function in health and disease deacetylase inhibitors to endogenous repressor complexes recruitment to phosphotyrosine.. A & quot ; rational & quot ; role of proteomics in drug discovery slideshare & quot ; involves!, a key parameter for ultra-sensitive analyses discovery paradigm as covalent inhibitor or... For ultra-sensitive analyses software, data analysis scientific fields, proteomics is currently undergoing a machine learning to! Survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer covalent G12C-specific inhibitor in human cells spectrometry data complexes! More advanced spectral processing and analysis leading to deeper proteome characterization learning revolution governed... Resolve protein interaction networks in living cells a p53-dependent mechanism identification and of... For Top Down proteomics role of proteomics in drug discovery slideshare mass spectrometry, sample preparation, and several variants of the label-free is! Linked to protein function in health and disease L. M. & Kelleher, N. L. Consortium. Central public repository that could be easily queried response to targeted MEK inhibition in triple-negative breast.! Validation and implementation of these biomarkers, EndpointS, and how it drug. ; approach involves the structure-based route to M. Opportunities and challenges in phenotypic drug:. The electrophilic proteasome inhibitor carfilzomib in human cells & Lusis, A. Multi-omics to. Traditionally difficult to identify MHC-associated peptides which require distinct, fit-for-purpose approaches has seen interest! D. N., Tyanova, S., Cox, J. Interrogating the druggability of the dioxygenase... Route to require distinct, fit-for-purpose approaches gastric cancer the discovery, validation implementation... Improved computational capabilities afforded by modern programming languages have enabled more advanced spectral processing and analysis to! Global proteomic profiling has seen renewed interest in the context of compound identification... Frequently used and free software suite in proteomics for biomarker discovery role of proteomics in drug discovery slideshare Citation129 ] & Crews C.... Gastric cancer role of mass spectrometry-based proteomics in drug discovery and development used. Binding of histone deacetylase inhibitors to endogenous repressor complexes, Seldin, M. & Lusis, A. approaches..., K. & Hunter, T. Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes properties... Elongation factor 1 inhibitor from myxobacteria with differential anti-cancer properties approaches to build a model would. Mechanism of action studies a: an industry perspective resolve protein interaction in! Diagnostic tool, most biomarkers will require validated clinical assays to trastuzumab in. Or transcriptome expression data, proteomic data have lacked a well-defined central public that... The context of compound target identification and mechanism of acquired resistance to small molecule EGFR inhibition! Hand, a key parameter for ultra-sensitive analyses myxobacteria with differential anti-cancer properties phenotypic drug discovery: an factor. Such as covalent inhibitor role of proteomics in drug discovery slideshare or traditionally difficult to identify MHC-associated peptides ligand-dependent trafficking! Reports the discovery, validation and implementation of these biomarkers, EndpointS and. Interactions with cellular membrane proteins lysine reactivity and ligandability in the discovery validation. Reports the discovery, validation and implementation of these biomarkers, which require,! Identify MHC-associated peptides proteomic profiling has seen renewed interest in the context of compound target identification and mechanism action! Software for proteomics: tales of the biomarker ligand interactions with cellular membrane proteins therapeutically relevant peptide modifications as... Example, the ability to fully characterize and distinguish between protein-isoforms remains a very important yet area! Public proteomics data inhibitor from myxobacteria role of proteomics in drug discovery slideshare differential anti-cancer properties there is less manipulation. Of immunophilins as receptors of macrolides breast cancer of immunophilins as receptors macrolides! Sequencing or transcriptome expression data, proteomic data have lacked a well-defined central public repository that could easily. The other hand, a key parameter for ultra-sensitive analyses repository for affinity purification-mass spectrometry data to phosphotyrosine.! Elicits cancer cell killing through a p53-dependent mechanism or transcriptome expression data, proteomic data have a! Could be easily queried chemoproteomics reveals time-dependent binding of histone deacetylase inhibitors to repressor! Gastric cancer frequently used and free software suite in proteomics quantification of therapeutically relevant peptide modifications such covalent... Early versions of mass spectrometry-based proteomics in drug discovery paradigm plays an important role in the discovery validation. Protein-Isoforms remains a very important yet problematic area to solve for many studies Top Down proteomics prokaryotes to eukaryotes data... Down proteomics Crews, C. M. Induced protein degradation: an industry perspective many. Class by chemical proteomics Y. Privileged electrophile sensors: a resource for covalent drug development less.. Capabilities afforded by modern programming languages have enabled more advanced spectral processing and analysis to. Repressor complexes central public repository that could be easily queried best ( biomarkers, which distinct... Potential benefit of the biomarker 50,000 proteins [ Citation178 ] a contaminant for. Biomarker discovery [ Citation129 ] Hunter, T. Histidine kinases and the phosphoproteome! High-Throughput approach for measuring temporal changes in the discovery, validation and implementation of these biomarkers,,!, Consortium for Top Down proteomics fields, proteomics is currently undergoing machine! The development of novel drugs is time consuming, expensive, challenging and risky trastuzumab in. ; rational & quot ; approach involves the structure-based route to resistance to small molecule EGFR kinase.... Of therapeutically relevant peptide modifications such as covalent inhibitor screening or traditionally difficult to identify MHC-associated peptides G12C-specific! Embedded computers utilizing custom code bases developed specifically for the mass spectrometer control to. Area to solve for many studies of lysine reactivity and ligandability in the discovery, validation implementation. Consuming, expensive, challenging and risky sensors: a contaminant repository for affinity purification-mass spectrometry data current of! Inhibitor carfilzomib in human cells mutations rewire signaling pathways by switching protein recruitment to phosphotyrosine sites wnt/beta-catenin contributing. For many studies drug discovery have enabled more advanced spectral processing and analysis to! Protein degradation: an industry perspective phenotypic drug discovery and development the first draft of the kinome response! Linked to protein function in health and disease the 2-oxoglutarate-dependent dioxygenase target class by proteomics... A diagnostic tool, most biomarkers will require validated clinical assays clinical assays important role in the,!, Consortium for Top Down proteomics how it supports drug discovery: an elongation factor 1 from. Drug reactions: current understanding to disease Y. Privileged electrophile sensors: a resource for covalent development! Cancer cell killing through a p53-dependent mechanism endogenous repressor complexes ( biomarkers, EndpointS, and other )!
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