Proteomes in Drug Development

A special issue of Proteomes (ISSN 2227-7382).

Deadline for manuscript submissions: closed (31 August 2016) | Viewed by 22207

Special Issue Editor

Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Interests: drug-protein interactions; chemical proteomics; systems chemical biology; polypharmacology; targeted and combination therapy; signaling pathways and networks.

Special Issue Information

Dear Colleagues,

In recent years there has been a shift in drug discovery and development from more traditional target-centric approaches towards viewing a drug and its target(s) in a broader biological context earlier in the development process. Drug efficacy, toxicity, and mechanisms of action and resistance are early on being evaluated on the cellular and organismal level using phenotypic screening and systems biology approaches. Furthermore, the transformative power of deep sequencing technologies has reminded us of the necessity of biomarker development for companion diagnostic-supported therapies. Enabled by massive technological advances in instrumentation, methodology, and data analysis over the last decade, mass spectrometry- and antibody array-based proteomic methods have proven to be powerful tools, which provide important global, unbiased and dynamic insight into these aspects. As a consequence, proteomics is these days widely applied to complement biochemical, pharmacological and genomic information.

This Special Issue on "Proteomes in Drug Development" will showcase new developments, highlights and applications of diverse proteomic approaches in the context of drug discovery and development. It will furthermore illustrate how proteomics is making essential contributions to a multi-layered, systems-level view of drug action, toxicity, and resistance, ultimately leading to a better understanding of the engaged biological targets, processes and networks that underlie the complexity of the majority of human diseases.

Dr. Uwe Rix
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Proteomes is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mechanism of action
  • biomarker
  • target identification
  • polypharmacology
  • systems biology
  • post-translational modifications
  • signalling
  • adaptive resistance
  • acquired resistance
  • expression signatures
  • protein quantification
  • activity profiling

Published Papers (2 papers)

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Research

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Article
Activity-Based Proteomics Reveals Heterogeneous Kinome and ATP-Binding Proteome Responses to MEK Inhibition in KRAS Mutant Lung Cancer
by Jae-Young Kim, Paul A. Stewart, Adam L. Borne, Bin Fang, Eric A. Welsh, Yian Ann Chen, Steven A. Eschrich, John M. Koomen and Eric B. Haura
Proteomes 2016, 4(2), 16; https://doi.org/10.3390/proteomes4020016 - 27 Apr 2016
Cited by 6 | Viewed by 6171
Abstract
One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level [...] Read more.
One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level profiling of drug-induced alterations in ATP-binding proteomes could offer novel insights into adaptive responses. Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS. We observed strikingly unique ATP-binding proteome responses to MEK inhibition, which revealed heterogeneous drug-induced pathway signatures in each cell line. We also identified diverse kinome responses, indicating each cell adapts to MEK inhibition in unique ways. Despite the heterogeneity of kinome responses, decreased probe labeling of mitotic kinases and an increase of kinases linked to autophagy were identified to be common responses. Taken together, our study revealed a diversity of adaptive ATP-binding proteome and kinome responses to MEK inhibition in KRAS mutant lung cancer cells, and our study further demonstrated the utility of our approach to identify potential candidates of targetable ATP-binding enzymes involved in adaptive resistance and to develop rational drug combinations. Full article
(This article belongs to the Special Issue Proteomes in Drug Development)
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Review

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Review
“Omics”-Informed Drug and Biomarker Discovery: Opportunities, Challenges and Future Perspectives
by Holly Matthews, James Hanison and Niroshini Nirmalan
Proteomes 2016, 4(3), 28; https://doi.org/10.3390/proteomes4030028 - 12 Sep 2016
Cited by 123 | Viewed by 15579
Abstract
The pharmaceutical industry faces unsustainable program failure despite significant increases in investment. Dwindling discovery pipelines, rapidly expanding R&D budgets and increasing regulatory control, predict significant gaps in the future drug markets. The cumulative duration of discovery from concept to commercialisation is unacceptably lengthy, [...] Read more.
The pharmaceutical industry faces unsustainable program failure despite significant increases in investment. Dwindling discovery pipelines, rapidly expanding R&D budgets and increasing regulatory control, predict significant gaps in the future drug markets. The cumulative duration of discovery from concept to commercialisation is unacceptably lengthy, and adds to the deepening crisis. Existing animal models predicting clinical translations are simplistic, highly reductionist and, therefore, not fit for purpose. The catastrophic consequences of ever-increasing attrition rates are most likely to be felt in the developing world, where resistance acquisition by killer diseases like malaria, tuberculosis and HIV have paced far ahead of new drug discovery. The coming of age of Omics-based applications makes available a formidable technological resource to further expand our knowledge of the complexities of human disease. The standardisation, analysis and comprehensive collation of the “data-heavy” outputs of these sciences are indeed challenging. A renewed focus on increasing reproducibility by understanding inherent biological, methodological, technical and analytical variables is crucial if reliable and useful inferences with potential for translation are to be achieved. The individual Omics sciences—genomics, transcriptomics, proteomics and metabolomics—have the singular advantage of being complimentary for cross validation, and together could potentially enable a much-needed systems biology perspective of the perturbations underlying disease processes. If current adverse trends are to be reversed, it is imperative that a shift in the R&D focus from speed to quality is achieved. In this review, we discuss the potential implications of recent Omics-based advances for the drug development process. Full article
(This article belongs to the Special Issue Proteomes in Drug Development)
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