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  • 1
    Abstract: As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
    Type of Publication: Journal article published
    PubMed ID: 29227286
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  • 2
    Abstract: Many protein kinases are valid drug targets in oncology because they are key components of signal transduction pathways. The number of clinical kinase inhibitors is on the rise, but these molecules often exhibit polypharmacology, potentially eliciting desired and toxic effects. Therefore, a comprehensive assessment of a compound's target space is desirable for a better understanding of its biological effects. The enzyme ferrochelatase (FECH) catalyzes the conversion of protoporphyrin IX into heme and was recently found to be an off-target of the BRAF inhibitor Vemurafenib, likely explaining the phototoxicity associated with this drug in melanoma patients. This raises the question of whether FECH binding is a more general feature of kinase inhibitors. To address this, we applied a chemical proteomics approach using kinobeads to evaluate 226 clinical kinase inhibitors for their ability to bind FECH. Surprisingly, low or submicromolar FECH binding was detected for 29 of all compounds tested and isothermal dose response measurements confirmed target engagement in cells. We also show that Vemurafenib, Linsitinib, Neratinib, and MK-2461 reduce heme levels in K562 cells, verifying that drug binding leads to a loss of FECH activity. Further biochemical and docking experiments identified the protoporphyrin pocket in FECH as one major drug binding site. Since the genetic loss of FECH activity leads to photosensitivity in humans, our data strongly suggest that FECH inhibition by kinase inhibitors is the molecular mechanism triggering photosensitivity in patients. We therefore suggest that a FECH assay should generally be part of the preclinical molecular toxicology package for the development of kinase inhibitors.
    Type of Publication: Journal article published
    PubMed ID: 26863403
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  • 3
    Keywords: QUANTIFICATION ; SYSTEMS ; IDENTIFICATION ; resistance ; CHRONIC MYELOGENOUS LEUKEMIA ; imatinib ; KINASE INHIBITORS ; PHOTOSENSITIVITY ; KINOME ; TARGET ENGAGEMENT
    Abstract: The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity.
    Type of Publication: Journal article published
    PubMed ID: 25278616
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  • 4
    Keywords: human ; NEW-YORK ; PROTEIN ; USA ; microbiology ; biotechnology
    Type of Publication: Journal article published
    PubMed ID: 18259167
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  • 5
    Publication Date: 2014-10-04
    Description: The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Savitski, Mikhail M -- Reinhard, Friedrich B M -- Franken, Holger -- Werner, Thilo -- Savitski, Maria Falth -- Eberhard, Dirk -- Martinez Molina, Daniel -- Jafari, Rozbeh -- Dovega, Rebecca Bakszt -- Klaeger, Susan -- Kuster, Bernhard -- Nordlund, Par -- Bantscheff, Marcus -- Drewes, Gerard -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):1255784. doi: 10.1126/science.1255784. Epub 2014 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. mikhail.m.savitski@gsk.com marcus.x.bantscheff@gsk.com gerard.c.drewes@gsk.com. ; Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. ; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. ; Department of Proteomics and Bioanalytics, Technische Universitat Munchen, Emil Erlenmeyer Forum 5, Freising, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. ; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Centre for Biomedical Structural Biology, Nanyang Technological University, Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278616" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Antineoplastic Agents/*pharmacology ; Hot Temperature ; Humans ; K562 Cells ; Ligands ; Protein Binding ; Protein Denaturation ; Protein Stability ; Proteome/*drug effects ; Proteomics/*methods
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2011-10-04
    Description: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679520/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679520/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Mark A -- Prinjha, Rab K -- Dittmann, Antje -- Giotopoulos, George -- Bantscheff, Marcus -- Chan, Wai-In -- Robson, Samuel C -- Chung, Chun-wa -- Hopf, Carsten -- Savitski, Mikhail M -- Huthmacher, Carola -- Gudgin, Emma -- Lugo, Dave -- Beinke, Soren -- Chapman, Trevor D -- Roberts, Emma J -- Soden, Peter E -- Auger, Kurt R -- Mirguet, Olivier -- Doehner, Konstanze -- Delwel, Ruud -- Burnett, Alan K -- Jeffrey, Phillip -- Drewes, Gerard -- Lee, Kevin -- Huntly, Brian J P -- Kouzarides, Tony -- 092096/Wellcome Trust/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- G116/187/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Oct 2;478(7370):529-33. doi: 10.1038/nature10509.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964340" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Chromatin/genetics/*metabolism ; Chromatin Immunoprecipitation ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Heterocyclic Compounds with 4 or More Rings/pharmacology/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Myeloid-Lymphoid Leukemia Protein/*metabolism ; Oncogene Proteins, Fusion/*metabolism ; Protein Binding/drug effects ; Proteomics ; Transcription Factors/*antagonists & inhibitors/*metabolism ; Transcription, Genetic/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-10-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kruidenier, Laurens -- Chung, Chun-wa -- Cheng, Zhongjun -- Liddle, John -- Che, KaHing -- Joberty, Gerard -- Bantscheff, Marcus -- Bountra, Chas -- Bridges, Angela -- Diallo, Hawa -- Eberhard, Dirk -- Hutchinson, Sue -- Jones, Emma -- Katso, Roy -- Leveridge, Melanie -- Mander, Palwinder K -- Mosley, Julie -- Ramirez-Molina, Cesar -- Rowland, Paul -- Schofield, Christopher J -- Sheppard, Robert J -- Smith, Julia E -- Swales, Catherine -- Tanner, Robert -- Thomas, Pamela -- Tumber, Anthony -- Drewes, Gerard -- Oppermann, Udo -- Patel, Dinshaw J -- Lee, Kevin -- Wilson, David M -- 092809/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Oct 2;514(7520):E2. doi: 10.1038/nature13689.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK. ; Platform Technology and Science, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK. ; Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. ; 1] Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK [2] Botnar Research Centre, NIHR Biomedical Research Unit, University of Oxford OX3 7LD, UK. ; Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany. ; Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK. ; Botnar Research Centre, NIHR Biomedical Research Unit, University of Oxford OX3 7LD, UK. ; 1] Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK [2] Pfizer, Biotherapeutics R&D, 200 Cambridgepark Drive, Cambridge, Massachusetts 02140, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25279927" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Enzyme Inhibitors/*pharmacology ; Humans ; Jumonji Domain-Containing Histone Demethylases/*antagonists & inhibitors ; Macrophages/*drug effects/*immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-05-30
    Description: Proteomes are characterized by large protein-abundance differences, cell-type- and time-dependent expression patterns and post-translational modifications, all of which carry biological information that is not accessible by genomics or transcriptomics. Here we present a mass-spectrometry-based draft of the human proteome and a public, high-performance, in-memory database for real-time analysis of terabytes of big data, called ProteomicsDB. The information assembled from human tissues, cell lines and body fluids enabled estimation of the size of the protein-coding genome, and identified organ-specific proteins and a large number of translated lincRNAs (long intergenic non-coding RNAs). Analysis of messenger RNA and protein-expression profiles of human tissues revealed conserved control of protein abundance, and integration of drug-sensitivity data enabled the identification of proteins predicting resistance or sensitivity. The proteome profiles also hold considerable promise for analysing the composition and stoichiometry of protein complexes. ProteomicsDB thus enables navigation of proteomes, provides biological insight and fosters the development of proteomic technology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilhelm, Mathias -- Schlegl, Judith -- Hahne, Hannes -- Moghaddas Gholami, Amin -- Lieberenz, Marcus -- Savitski, Mikhail M -- Ziegler, Emanuel -- Butzmann, Lars -- Gessulat, Siegfried -- Marx, Harald -- Mathieson, Toby -- Lemeer, Simone -- Schnatbaum, Karsten -- Reimer, Ulf -- Wenschuh, Holger -- Mollenhauer, Martin -- Slotta-Huspenina, Julia -- Boese, Joos-Hendrik -- Bantscheff, Marcus -- Gerstmair, Anja -- Faerber, Franz -- Kuster, Bernhard -- England -- Nature. 2014 May 29;509(7502):582-7. doi: 10.1038/nature13319.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Chair of Proteomics and Bioanalytics, Technische Universitat Munchen, Emil-Erlenmeyer Forum 5, 85354 Freising, Germany [2] SAP AG, Dietmar-Hopp-Allee 16, 69190 Walldorf, Germany [3]. ; 1] SAP AG, Dietmar-Hopp-Allee 16, 69190 Walldorf, Germany [2]. ; 1] Chair of Proteomics and Bioanalytics, Technische Universitat Munchen, Emil-Erlenmeyer Forum 5, 85354 Freising, Germany [2]. ; SAP AG, Dietmar-Hopp-Allee 16, 69190 Walldorf, Germany. ; Cellzome GmbH, Meyerhofstrasse 1, 69117 Heidelberg, Germany. ; Chair of Proteomics and Bioanalytics, Technische Universitat Munchen, Emil-Erlenmeyer Forum 5, 85354 Freising, Germany. ; JPT Peptide Technologies GmbH, Volmerstrasse 5, 12489 Berlin, Germany. ; Institute of Pathology, Technische Universitat Munchen, Trogerstrasse 18, 81675 Munchen, Germany. ; 1] Chair of Proteomics and Bioanalytics, Technische Universitat Munchen, Emil-Erlenmeyer Forum 5, 85354 Freising, Germany [2] Center for Integrated Protein Science Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870543" target="_blank"〉PubMed〈/a〉
    Keywords: Body Fluids/chemistry/metabolism ; Cell Line ; *Databases, Protein ; Gene Expression Profiling ; Genome, Human/genetics ; Humans ; *Mass Spectrometry ; Molecular Sequence Annotation ; Organ Specificity ; Proteome/*analysis/*chemistry/genetics/metabolism ; *Proteomics ; RNA, Messenger/analysis/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2012-07-31
    Description: The jumonji (JMJ) family of histone demethylases are Fe2+- and alpha-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691848/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691848/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kruidenier, Laurens -- Chung, Chun-wa -- Cheng, Zhongjun -- Liddle, John -- Che, KaHing -- Joberty, Gerard -- Bantscheff, Marcus -- Bountra, Chas -- Bridges, Angela -- Diallo, Hawa -- Eberhard, Dirk -- Hutchinson, Sue -- Jones, Emma -- Katso, Roy -- Leveridge, Melanie -- Mander, Palwinder K -- Mosley, Julie -- Ramirez-Molina, Cesar -- Rowland, Paul -- Schofield, Christopher J -- Sheppard, Robert J -- Smith, Julia E -- Swales, Catherine -- Tanner, Robert -- Thomas, Pamela -- Tumber, Anthony -- Drewes, Gerard -- Oppermann, Udo -- Patel, Dinshaw J -- Lee, Kevin -- Wilson, David M -- 092809/Wellcome Trust/United Kingdom -- 18358/Arthritis Research UK/United Kingdom -- P30 CA008748/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Aug 16;488(7411):404-8. doi: 10.1038/nature11262.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22842901" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Biocatalysis/drug effects ; Catalytic Domain ; Cells, Cultured ; Enzyme Inhibitors/metabolism/*pharmacology ; Evolution, Molecular ; Histones/chemistry/metabolism ; Humans ; Inhibitory Concentration 50 ; Jumonji Domain-Containing Histone Demethylases/*antagonists & ; inhibitors/chemistry/classification/metabolism ; Lysine/metabolism ; Macrophages/*drug effects/enzymology/*immunology/metabolism ; Methylation/drug effects ; Mice ; Models, Molecular ; Substrate Specificity ; Tumor Necrosis Factor-alpha/biosynthesis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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