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  1. Book ; Online ; Thesis: Identifizierung krankheitsassoziierter MHC-Liganden durch massenspektrometrische Verfahren

    Schirle, Markus

    2001  

    Author's details vorgelegt von Markus Schirle
    Language German
    Publishing country Germany
    Document type Book ; Online ; Thesis
    Thesis / German Habilitation thesis Tübingen, Univ., Diss., 2001
    Note Open Access
    HBZ-ID HT013921464
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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  2. Article ; Online: Characterizing Drug-Target Interactions: Shifting towards the Clinic.

    Schirle, Markus

    Trends in pharmacological sciences

    2020  Volume 41, Issue 5, Page(s) 295–297

    Abstract: Recently, Perrin et al. reported the application of thermal proteome profiling (TPP), a cellular thermal shift assay with an unbiased proteomics readout to complex tissue samples from model organisms and patient-derived whole blood. This study ... ...

    Abstract Recently, Perrin et al. reported the application of thermal proteome profiling (TPP), a cellular thermal shift assay with an unbiased proteomics readout to complex tissue samples from model organisms and patient-derived whole blood. This study demonstrates for the first time that TPP enables organ-specific drug target engagement and identification studies during the later stages of drug discovery and even in a clinical setting.
    MeSH term(s) Drug Delivery Systems ; Drug Discovery ; Humans ; Proteome ; Proteomics
    Chemical Substances Proteome
    Language English
    Publishing date 2020-03-16
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 282846-7
    ISSN 1873-3735 ; 0165-6147
    ISSN (online) 1873-3735
    ISSN 0165-6147
    DOI 10.1016/j.tips.2020.03.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1513: Show issues Location:
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    Zs.MG 6: Show issues

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  3. Article ; Online: Proteomics in the pharmaceutical and biotechnology industry: a look to the next decade.

    Lill, Jennie R / Mathews, William R / Rose, Christopher M / Schirle, Markus

    Expert review of proteomics

    2021  Volume 18, Issue 7, Page(s) 503–526

    Abstract: Introduction: 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 ... ...

    Abstract Introduction: 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. The field of proteomics is undergoing an inflection point, where new sensitive technologies are allowing intricate biological pathways to be better understood, and novel biochemical tools are pivoting us into a new era of chemical proteomics and biomarker discovery. In this review, we describe these areas of innovation, and discuss where the fields are headed in terms of fueling biotechnological and pharmacological research and discuss current gaps in the proteomic technology landscape.
    Areas covered: Single cell sequencing and single molecule sequencing. Chemoproteomics. Biological matrices and clinical samples including biomarkers. Computational tools including instrument control software, data analysis.
    Expert opinion: Proteomics will likely remain a key technology in the coming decade, but will have to evolve with respect to type and granularity of data, cost and throughput of data generation as well as integration with other technologies to fulfill its promise in drug discovery.
    MeSH term(s) Biomarkers ; Biotechnology ; Drug Discovery ; Pharmaceutical Preparations ; Proteomics
    Chemical Substances Biomarkers ; Pharmaceutical Preparations
    Language English
    Publishing date 2021-08-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2299100-1
    ISSN 1744-8387 ; 1478-9450
    ISSN (online) 1744-8387
    ISSN 1478-9450
    DOI 10.1080/14789450.2021.1962300
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  4. Article ; Online: Targeted Protein Degradation through E2 Recruitment.

    Forte, Nafsika / Dovala, Dustin / Hesse, Matthew J / McKenna, Jeffrey M / Tallarico, John A / Schirle, Markus / Nomura, Daniel K

    ACS chemical biology

    2023  Volume 18, Issue 4, Page(s) 897–904

    Abstract: Targeted protein degradation (TPD) with proteolysis targeting chimeras (PROTACs), heterobifunctional compounds consisting of protein targeting ligands linked to recruiters of E3 ubiquitin ligases, has arisen as a powerful therapeutic modality to induce ... ...

    Abstract Targeted protein degradation (TPD) with proteolysis targeting chimeras (PROTACs), heterobifunctional compounds consisting of protein targeting ligands linked to recruiters of E3 ubiquitin ligases, has arisen as a powerful therapeutic modality to induce the proximity of target proteins with E3 ligases to ubiquitinate and degrade specific proteins in cells. Thus far, PROTACs have primarily exploited the recruitment of E3 ubiquitin ligases or their substrate adapter proteins but have not exploited the recruitment of more core components of the ubiquitin-proteasome system (UPS). In this study, we used covalent chemoproteomic approaches to discover a covalent recruiter against the E2 ubiquitin conjugating enzyme UBE2D─EN67─that targets an allosteric cysteine, C111, without affecting the enzymatic activity of the protein. We demonstrated that this UBE2D recruiter could be used in heterobifunctional degraders to degrade neo-substrate targets in a UBE2D-dependent manner, including BRD4 and the androgen receptor. Overall, our data highlight the potential for the recruitment of core components of the UPS machinery, such as E2 ubiquitin conjugating enzymes, for TPD, and underscore the utility of covalent chemoproteomic strategies for identifying novel recruiters for additional components of the UPS.
    MeSH term(s) Ligands ; Nuclear Proteins/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Transcription Factors/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/chemistry ; Ubiquitin-Protein Ligases/metabolism ; Proteolysis Targeting Chimera/chemistry ; Proteolysis Targeting Chimera/metabolism
    Chemical Substances Ligands ; Nuclear Proteins ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Transcription Factors ; Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteolysis Targeting Chimera
    Language English
    Publishing date 2023-03-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.3c00040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB.

    King, Elizabeth A / Cho, Yoojin / Hsu, Nathan S / Dovala, Dustin / McKenna, Jeffrey M / Tallarico, John A / Schirle, Markus / Nomura, Daniel K

    Cell chemical biology

    2023  Volume 30, Issue 4, Page(s) 394–402.e9

    Abstract: Targeted protein degradation has arisen as a powerful therapeutic modality for degrading disease targets. While proteolysis-targeting chimera (PROTAC) design is more modular, the discovery of molecular glue degraders has been more challenging. Here, we ... ...

    Abstract Targeted protein degradation has arisen as a powerful therapeutic modality for degrading disease targets. While proteolysis-targeting chimera (PROTAC) design is more modular, the discovery of molecular glue degraders has been more challenging. Here, we have coupled the phenotypic screening of a covalent ligand library with chemoproteomic approaches to rapidly discover a covalent molecular glue degrader and associated mechanisms. We have identified a cysteine-reactive covalent ligand EN450 that impairs leukemia cell viability in a NEDDylation and proteasome-dependent manner. Chemoproteomic profiling revealed covalent interaction of EN450 with an allosteric C111 in the E2 ubiquitin-conjugating enzyme UBE2D. Quantitative proteomic profiling revealed the degradation of the oncogenic transcription factor NFKB1 as a putative degradation target. Our study thus puts forth the discovery of a covalent molecular glue degrader that uniquely induced the proximity of an E2 with a transcription factor to induce its degradation in cancer cells.
    MeSH term(s) NF-kappa B/metabolism ; Ligands ; Proteomics ; Proteolysis ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances NF-kappa B ; Ligands ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2023-03-09
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2023.02.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Ophiobolin A Covalently Targets Mitochondrial Complex IV Leading to Metabolic Collapse in Cancer Cells.

    Gowans, Flor A / Thach, Danny Q / Zhu, Zhouyang / Wang, Yangzhi / Altamirano Poblano, Belen E / Dovala, Dustin / Tallarico, John A / McKenna, Jeffrey M / Schirle, Markus / Maimone, Thomas J / Nomura, Daniel K

    ACS chemical biology

    2024  

    Abstract: Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anticancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and ... ...

    Abstract Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anticancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of the OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets: lysine-72 of cytochrome c oxidase subunit 5A (COX5A) and cysteine-53 of mitochondrial hypoxia induced gene 1 domain family member 2A (HIGD2A). These two subunit proteins are part of complex IV (cytochrome C oxidase) within the electron transport chain and contributed significantly to the antiproliferative activity of OPA. OPA activated mitochondrial respiration in a COX5A- and HIGD2A-dependent manner, leading to an initial spike in mitochondrial ATP and heightened mitochondrial oxidative stress. OPA compromised mitochondrial membrane potential, ultimately leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anticancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death.
    Language English
    Publishing date 2024-05-13
    Publishing country United States
    Document type Journal Article
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.4c00064
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Identifying compound efficacy targets in phenotypic drug discovery.

    Schirle, Markus / Jenkins, Jeremy L

    Drug discovery today

    2016  Volume 21, Issue 1, Page(s) 82–89

    Abstract: The identification of the efficacy target(s) for hits from phenotypic compound screens remains a key step to progress compounds into drug development. In addition to efficacy targets, the characterization of epistatic proteins influencing compound ... ...

    Abstract The identification of the efficacy target(s) for hits from phenotypic compound screens remains a key step to progress compounds into drug development. In addition to efficacy targets, the characterization of epistatic proteins influencing compound activity often facilitates the elucidation of the underlying mechanism of action; and, further, early determination of off-targets that cause potentially unwanted secondary phenotypes helps in assessing potential liabilities. This short review discusses the most important technologies currently available for characterizing the direct and indirect target space of bioactive compounds following phenotypic screening. We present a comprehensive strategy employing complementary approaches to balance individual technology strengths and weaknesses.
    MeSH term(s) Drug Discovery/methods ; Humans ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/chemistry ; Phenotype ; Proteins/metabolism
    Chemical Substances Pharmaceutical Preparations ; Proteins
    Language English
    Publishing date 2016-01
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2015.08.001
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  8. Article ; Online: Correction to "Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications".

    Henning, Nathaniel J / Manford, Andrew G / Spradlin, Jessica N / Brittain, Scott M / Zhang, Erika / McKenna, Jeffrey M / Tallarico, John A / Schirle, Markus / Rape, Michael / Nomura, Daniel K

    Journal of the American Chemical Society

    2023  Volume 145, Issue 38, Page(s) 21142

    Language English
    Publishing date 2023-09-14
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/jacs.3c09174
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Bonn / Germany

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  9. Article: Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells.

    Gowans, Flor A / Thach, Danny Q / Wang, Yangzhi / Altamirano Poblano, Belen E / Dovala, Dustin / Tallarico, John A / McKenna, Jeffrey M / Schirle, Markus / Maimone, Thomas J / Nomura, Daniel K

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and ... ...

    Abstract Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets-cysteine C53 of HIG2DA and lysine K72 of COX5A-that are part of complex IV of the electron transport chain and contributed significantly to the anti-proliferative activity. OPA activated mitochondrial respiration in a HIG2DA and COX5A-dependent manner, led to an initial spike in mitochondrial ATP, but then compromised mitochondrial membrane potential leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anti-cancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death.
    Language English
    Publishing date 2023-03-09
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.09.531918
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Identification of tumor-associated HLA-ligands in the post-genomic era.

    Schirle, Markus

    Journal of hematotherapy & stem cell research

    2002  Volume 11, Issue 6, Page(s) 873–881

    Abstract: Over 10 years ago, the identification of the first tumor-specific T cell epitope shed light on the molecular principles underlying the phenomenon of tumor eradication by the immune system. Since then, a considerable number of different approaches for ... ...

    Abstract Over 10 years ago, the identification of the first tumor-specific T cell epitope shed light on the molecular principles underlying the phenomenon of tumor eradication by the immune system. Since then, a considerable number of different approaches for this task have been introduced and employed successfully, reflecting the growing knowledge about the cellular processes preceding antigen presentation as well as significant technical developments. This review tries to give an overview over available conventional strategies as well as current developments that utilize the potent large-scale screening tools of the post-genomic era.
    MeSH term(s) Animals ; Antigens, Neoplasm/analysis ; Antigens, Neoplasm/immunology ; Drug Evaluation, Preclinical/methods ; Epitopes/analysis ; HLA Antigens/immunology ; Humans ; T-Lymphocytes/immunology
    Chemical Substances Antigens, Neoplasm ; Epitopes ; HLA Antigens
    Language English
    Publishing date 2002-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1494547-2
    ISSN 1525-8165
    ISSN 1525-8165
    DOI 10.1089/152581602321080538
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3616: Show issues Location:
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