Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma. View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-04-08

AUTHORS

Yan Song, Paul M C Park, Lei Wu, Arghya Ray, Sarah Picaud, Deyao Li, Virangika K Wimalasena, Ting Du, Panagis Filippakopoulos, Kenneth C Anderson, Jun Qi, Dharminder Chauhan

ABSTRACT

Proteasome inhibition is an effective treatment for multiple myeloma (MM); however, targeting different components of the ubiquitin-proteasome system (UPS) remains elusive. Our RNA-interference studies identified proteasome-associated ubiquitin-receptor Rpn13 as a mediator of MM cell growth and survival. Here, we developed the first degrader of Rpn13, WL40, using a small-molecule-induced targeted protein degradation strategy to selectively degrade this component of the UPS. WL40 was synthesized by linking the Rpn13 covalent inhibitor RA190 with the cereblon (CRBN) binding ligand thalidomide. We show that WL40 binds to both Rpn13 and CRBN and triggers degradation of cellular Rpn13, and is therefore first-in-class in exploiting a covalent inhibitor for the development of degraders. Biochemical and cellular studies show that WL40-induced Rpn13 degradation is both CRBN E3 ligase- and Rpn13-dependent. Importantly, WL40 decreases viability in MM cell lines and patient MM cells, even those resistant to bortezomib. Mechanistically, WL40 interrupts Rpn13 function and activates caspase apoptotic cascade, ER stress response and p53/p21 signaling. In animal model studies, WL40 inhibits xenografted human MM cell growth and prolongs survival. Overall, our data show the development of the first UbR Rpn13 degrader with potent anti-MM activity, and provide proof of principle for the development of degraders targeting components of the UPS for therapeutic application. More... »

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41375-019-0467-z

DOI

http://dx.doi.org/10.1038/s41375-019-0467-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1113300798

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30962579


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1112", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Oncology and Carcinogenesis", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Medical and Health Sciences", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "name": [
            "LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Song", 
        "givenName": "Yan", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Park", 
        "givenName": "Paul M C", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Wu", 
        "givenName": "Lei", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Ray", 
        "givenName": "Arghya", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Oxford", 
          "id": "https://www.grid.ac/institutes/grid.4991.5", 
          "name": [
            "University of Oxford, Oxford, UK."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Picaud", 
        "givenName": "Sarah", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Li", 
        "givenName": "Deyao", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Wimalasena", 
        "givenName": "Virangika K", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Du", 
        "givenName": "Ting", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Oxford", 
          "id": "https://www.grid.ac/institutes/grid.4991.5", 
          "name": [
            "University of Oxford, Oxford, UK."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Filippakopoulos", 
        "givenName": "Panagis", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Kenneth_Anderson@dfci.harvard.edu."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Anderson", 
        "givenName": "Kenneth C", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA. Jun_Qi@dfci.harvard.edu."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Qi", 
        "givenName": "Jun", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "name": [
            "LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Dharminder_Chauhan@dfci.harvard.edu."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Chauhan", 
        "givenName": "Dharminder", 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "https://doi.org/10.1158/1078-0432.ccr-12-3752", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1000439946"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1093/hmg/ddi312", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1001185591"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1093/hmg/ddi312", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1001185591"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/b978-0-12-407704-1.00005-1", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1003257664"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/leu.2016.97", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1006372404", 
          "https://doi.org/10.1038/leu.2016.97"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/1535-7163.mct-04-0338", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1007689239"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.sbi.2016.01.004", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1008904823"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/gcc.22262", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1009908512"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.141230798", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1010028896"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.molcel.2015.02.025", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1010589854"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.1244917", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1012224724"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature02263", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1012758273", 
          "https://doi.org/10.1038/nature02263"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature02263", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1012758273", 
          "https://doi.org/10.1038/nature02263"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1182/blood-2012-01-401794", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1014314116"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1136/gut.2007.143065", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1015712242"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1146/annurev-biochem-051810-094654", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1017846425"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.aab1433", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1019990583"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ccr.2013.11.001", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1023348529"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/jacs.5b02069", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1025221893"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1056/nejmoa030288", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1028177288"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ccr.2005.10.013", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1030150234"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ccr.2005.10.013", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1030150234"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/anie.201507978", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033234985"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ccr.2009.08.019", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033289074"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ccr.2009.08.019", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033289074"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nrc1361", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033550220", 
          "https://doi.org/10.1038/nrc1361"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nrc1361", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033550220", 
          "https://doi.org/10.1038/nrc1361"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/gcc.20592", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033758484"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1146/annurev.pharmtox.45.120403.100037", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033899181"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ccr.2012.08.007", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1035292014"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.chembiol.2015.05.009", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1038118204"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/anie.201503720", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1039261715"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.1177319", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1044064445"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.1177319", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1044064445"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1634/theoncologist.8-6-508", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1044258202"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/sj.cdd.4401702", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045451673", 
          "https://doi.org/10.1038/sj.cdd.4401702"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/sj.cdd.4401702", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045451673", 
          "https://doi.org/10.1038/sj.cdd.4401702"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/sj.cdd.4401702", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045451673", 
          "https://doi.org/10.1038/sj.cdd.4401702"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1182/blood-2005-03-1173", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1050947392"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature06924", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1052385095", 
          "https://doi.org/10.1038/nature06924"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.3892/or_00000368", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1071537173"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.6004/jnccn.2013.0199", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1078734503"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.6004/jnccn.2013.0199", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1078734503"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1082860421", 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/ncomms15540", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1085942910", 
          "https://doi.org/10.1038/ncomms15540"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.cbpa.2017.05.016", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1085961097"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.chembiol.2017.05.024", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1086124525"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.chembiol.2017.09.009", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1092620849"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.chembiol.2017.09.009", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1092620849"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/s41589-018-0055-y", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1104478464", 
          "https://doi.org/10.1038/s41589-018-0055-y"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/s41589-018-0055-y", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1104478464", 
          "https://doi.org/10.1038/s41589-018-0055-y"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/s41589-018-0055-y", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1104478464", 
          "https://doi.org/10.1038/s41589-018-0055-y"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/acsomega.8b01479", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1107253733"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1080/14656566.2018.1528229", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1109831867"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1080/14656566.2018.1528229", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1109831867"
        ], 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2019-04-08", 
    "datePublishedReg": "2019-04-08", 
    "description": "Proteasome inhibition is an effective treatment for multiple myeloma (MM); however, targeting different components of the ubiquitin-proteasome system (UPS) remains elusive. Our RNA-interference studies identified proteasome-associated ubiquitin-receptor Rpn13 as a mediator of MM cell growth and survival. Here, we developed the first degrader of Rpn13, WL40, using a small-molecule-induced targeted protein degradation strategy to selectively degrade this component of the UPS. WL40 was synthesized by linking the Rpn13 covalent inhibitor RA190 with the cereblon (CRBN) binding ligand thalidomide. We show that WL40 binds to both Rpn13 and CRBN and triggers degradation of cellular Rpn13, and is therefore first-in-class in exploiting a covalent inhibitor for the development of degraders. Biochemical and cellular studies show that WL40-induced Rpn13 degradation is both CRBN E3 ligase- and Rpn13-dependent. Importantly, WL40 decreases viability in MM cell lines and patient MM cells, even those resistant to bortezomib. Mechanistically, WL40 interrupts Rpn13 function and activates caspase apoptotic cascade, ER stress response and p53/p21 signaling. In animal model studies, WL40 inhibits xenografted human MM cell growth and prolongs survival. Overall, our data show the development of the first UbR Rpn13 degrader with potent anti-MM activity, and provide proof of principle for the development of degraders targeting components of the UPS for therapeutic application.", 
    "genre": "research_article", 
    "id": "sg:pub.10.1038/s41375-019-0467-z", 
    "inLanguage": [
      "en"
    ], 
    "isAccessibleForFree": false, 
    "isFundedItemOf": [
      {
        "id": "sg:grant.5476699", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2470343", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2440198", 
        "type": "MonetaryGrant"
      }
    ], 
    "isPartOf": [
      {
        "id": "sg:journal.1097065", 
        "issn": [
          "0887-6924", 
          "1476-5551"
        ], 
        "name": "Leukemia", 
        "type": "Periodical"
      }
    ], 
    "name": "Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma.", 
    "productId": [
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1038/s41375-019-0467-z"
        ]
      }, 
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1113300798"
        ]
      }, 
      {
        "name": "nlm_unique_id", 
        "type": "PropertyValue", 
        "value": [
          "8704895"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "30962579"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1038/s41375-019-0467-z", 
      "https://app.dimensions.ai/details/publication/pub.1113300798"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2019-04-16T06:23", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000377_0000000377/records_106819_00000003.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "http://www.nature.com/articles/s41375-019-0467-z"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s41375-019-0467-z'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s41375-019-0467-z'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41375-019-0467-z'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41375-019-0467-z'


 

This table displays all metadata directly associated to this object as RDF triples.

281 TRIPLES      20 PREDICATES      66 URIs      16 LITERALS      6 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1038/s41375-019-0467-z schema:about anzsrc-for:11
2 anzsrc-for:1112
3 schema:author N80745a15bc1a4a388342c15620ec953a
4 schema:citation sg:pub.10.1038/leu.2016.97
5 sg:pub.10.1038/nature02263
6 sg:pub.10.1038/nature06924
7 sg:pub.10.1038/ncomms15540
8 sg:pub.10.1038/nrc1361
9 sg:pub.10.1038/s41589-018-0055-y
10 sg:pub.10.1038/sj.cdd.4401702
11 https://app.dimensions.ai/details/publication/pub.1082860421
12 https://doi.org/10.1002/anie.201503720
13 https://doi.org/10.1002/anie.201507978
14 https://doi.org/10.1002/gcc.20592
15 https://doi.org/10.1002/gcc.22262
16 https://doi.org/10.1016/b978-0-12-407704-1.00005-1
17 https://doi.org/10.1016/j.cbpa.2017.05.016
18 https://doi.org/10.1016/j.ccr.2005.10.013
19 https://doi.org/10.1016/j.ccr.2009.08.019
20 https://doi.org/10.1016/j.ccr.2012.08.007
21 https://doi.org/10.1016/j.ccr.2013.11.001
22 https://doi.org/10.1016/j.chembiol.2015.05.009
23 https://doi.org/10.1016/j.chembiol.2017.05.024
24 https://doi.org/10.1016/j.chembiol.2017.09.009
25 https://doi.org/10.1016/j.molcel.2015.02.025
26 https://doi.org/10.1016/j.sbi.2016.01.004
27 https://doi.org/10.1021/acsomega.8b01479
28 https://doi.org/10.1021/jacs.5b02069
29 https://doi.org/10.1056/nejmoa030288
30 https://doi.org/10.1073/pnas.141230798
31 https://doi.org/10.1080/14656566.2018.1528229
32 https://doi.org/10.1093/hmg/ddi312
33 https://doi.org/10.1126/science.1177319
34 https://doi.org/10.1126/science.1244917
35 https://doi.org/10.1126/science.aab1433
36 https://doi.org/10.1136/gut.2007.143065
37 https://doi.org/10.1146/annurev-biochem-051810-094654
38 https://doi.org/10.1146/annurev.pharmtox.45.120403.100037
39 https://doi.org/10.1158/1078-0432.ccr-12-3752
40 https://doi.org/10.1158/1535-7163.mct-04-0338
41 https://doi.org/10.1182/blood-2005-03-1173
42 https://doi.org/10.1182/blood-2012-01-401794
43 https://doi.org/10.1634/theoncologist.8-6-508
44 https://doi.org/10.3892/or_00000368
45 https://doi.org/10.6004/jnccn.2013.0199
46 schema:datePublished 2019-04-08
47 schema:datePublishedReg 2019-04-08
48 schema:description Proteasome inhibition is an effective treatment for multiple myeloma (MM); however, targeting different components of the ubiquitin-proteasome system (UPS) remains elusive. Our RNA-interference studies identified proteasome-associated ubiquitin-receptor Rpn13 as a mediator of MM cell growth and survival. Here, we developed the first degrader of Rpn13, WL40, using a small-molecule-induced targeted protein degradation strategy to selectively degrade this component of the UPS. WL40 was synthesized by linking the Rpn13 covalent inhibitor RA190 with the cereblon (CRBN) binding ligand thalidomide. We show that WL40 binds to both Rpn13 and CRBN and triggers degradation of cellular Rpn13, and is therefore first-in-class in exploiting a covalent inhibitor for the development of degraders. Biochemical and cellular studies show that WL40-induced Rpn13 degradation is both CRBN E3 ligase- and Rpn13-dependent. Importantly, WL40 decreases viability in MM cell lines and patient MM cells, even those resistant to bortezomib. Mechanistically, WL40 interrupts Rpn13 function and activates caspase apoptotic cascade, ER stress response and p53/p21 signaling. In animal model studies, WL40 inhibits xenografted human MM cell growth and prolongs survival. Overall, our data show the development of the first UbR Rpn13 degrader with potent anti-MM activity, and provide proof of principle for the development of degraders targeting components of the UPS for therapeutic application.
49 schema:genre research_article
50 schema:inLanguage en
51 schema:isAccessibleForFree false
52 schema:isPartOf sg:journal.1097065
53 schema:name Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma.
54 schema:productId N184e1b20da8042b59c2d4a94f96d1495
55 N481713579c9c44b59538e4d6a09015bb
56 N92da832382664de3956b70540b0ad609
57 Nb6387fdc91654452bf806527f4dce9c2
58 schema:sameAs https://app.dimensions.ai/details/publication/pub.1113300798
59 https://doi.org/10.1038/s41375-019-0467-z
60 schema:sdDatePublished 2019-04-16T06:23
61 schema:sdLicense https://scigraph.springernature.com/explorer/license/
62 schema:sdPublisher Nf080bb2578cb4f3ca15016f3834c9748
63 schema:url http://www.nature.com/articles/s41375-019-0467-z
64 sgo:license sg:explorer/license/
65 sgo:sdDataset articles
66 rdf:type schema:ScholarlyArticle
67 N05f0c55ead08462d832522bacad628c1 rdf:first Nc19a6ed256b14df2b0804db1b107e631
68 rdf:rest N65958b257fed4a8a89a6fe5589fe0e11
69 N083fae36b93d42f5bd5b37a1a688540a rdf:first Nd1177a005f8a4b68bace344052cbc3da
70 rdf:rest N297e22e7dafd431bab23b23758530cec
71 N1391ba4c0b40493cb821175db5a75467 schema:affiliation N9c8445e1c42946e9b16a60033e4a609b
72 schema:familyName Song
73 schema:givenName Yan
74 rdf:type schema:Person
75 N184e1b20da8042b59c2d4a94f96d1495 schema:name nlm_unique_id
76 schema:value 8704895
77 rdf:type schema:PropertyValue
78 N1b9a5231971148f2a87ca386d825cfec schema:name Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.
79 rdf:type schema:Organization
80 N1e4671d9da8a4df58edfca4f7bf5aa9c schema:affiliation N82c46dd56999434a85770c61ca88eca8
81 schema:familyName Qi
82 schema:givenName Jun
83 rdf:type schema:Person
84 N297e22e7dafd431bab23b23758530cec rdf:first N779a502510014620862fc36889dced18
85 rdf:rest N4404028081f1444e9128d6c9d3a9dd5d
86 N32ae6a3f8c9d437c96884335687494a9 rdf:first N1e4671d9da8a4df58edfca4f7bf5aa9c
87 rdf:rest N71833d87a0dd4dab9139bb7de0f60bd3
88 N411cc228d9974d019d98d8b915bbe6d5 rdf:first Ne9c0858cb34142459e736bba4237bbdd
89 rdf:rest N880f58e6d0824c0f9e574d5888f3b784
90 N4404028081f1444e9128d6c9d3a9dd5d rdf:first N696124f0e30543218917a9352b714a9d
91 rdf:rest N566d8dd7bb7645cbb56dbdcb4e9ef8a1
92 N481713579c9c44b59538e4d6a09015bb schema:name doi
93 schema:value 10.1038/s41375-019-0467-z
94 rdf:type schema:PropertyValue
95 N566d8dd7bb7645cbb56dbdcb4e9ef8a1 rdf:first Nae4d16eb26a443c38cfadb8e3fc3025f
96 rdf:rest N05f0c55ead08462d832522bacad628c1
97 N5c259e6ef87e4b79ba46f3f94e01a713 schema:name Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.
98 rdf:type schema:Organization
99 N63aad1a7c6cd47d997760ee81004e467 schema:name LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
100 rdf:type schema:Organization
101 N65958b257fed4a8a89a6fe5589fe0e11 rdf:first N9bd5abba81e94cbaa6ca862e2638e169
102 rdf:rest N411cc228d9974d019d98d8b915bbe6d5
103 N66bbf36970e749a69cf8a20507aa4623 schema:name Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.
104 rdf:type schema:Organization
105 N67ac4c19e4c0409d9b73516b7c9d950a schema:name Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.
106 rdf:type schema:Organization
107 N696124f0e30543218917a9352b714a9d schema:affiliation https://www.grid.ac/institutes/grid.4991.5
108 schema:familyName Picaud
109 schema:givenName Sarah
110 rdf:type schema:Person
111 N7071e650580845059d232ccb5877d99e schema:name LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Dharminder_Chauhan@dfci.harvard.edu.
112 rdf:type schema:Organization
113 N71833d87a0dd4dab9139bb7de0f60bd3 rdf:first Nb183176c14d14a9cba1653b64a682d2f
114 rdf:rest rdf:nil
115 N756b8085ed124f8198e563f8059e4f01 schema:affiliation Na7b79a9d43774331a175c1675524aca4
116 schema:familyName Anderson
117 schema:givenName Kenneth C
118 rdf:type schema:Person
119 N779a502510014620862fc36889dced18 schema:affiliation N63aad1a7c6cd47d997760ee81004e467
120 schema:familyName Ray
121 schema:givenName Arghya
122 rdf:type schema:Person
123 N80745a15bc1a4a388342c15620ec953a rdf:first N1391ba4c0b40493cb821175db5a75467
124 rdf:rest Naa63a9e77a684032a706546aeea2ba5d
125 N82c46dd56999434a85770c61ca88eca8 schema:name Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA. Jun_Qi@dfci.harvard.edu.
126 rdf:type schema:Organization
127 N880f58e6d0824c0f9e574d5888f3b784 rdf:first N756b8085ed124f8198e563f8059e4f01
128 rdf:rest N32ae6a3f8c9d437c96884335687494a9
129 N92da832382664de3956b70540b0ad609 schema:name pubmed_id
130 schema:value 30962579
131 rdf:type schema:PropertyValue
132 N9bd5abba81e94cbaa6ca862e2638e169 schema:affiliation Nc73ddfb8ee3a426ea2e9df07374e08ee
133 schema:familyName Du
134 schema:givenName Ting
135 rdf:type schema:Person
136 N9c8445e1c42946e9b16a60033e4a609b schema:name LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
137 rdf:type schema:Organization
138 N9f5d7d6091ef497dbbc1f4f206734db9 schema:affiliation N67ac4c19e4c0409d9b73516b7c9d950a
139 schema:familyName Park
140 schema:givenName Paul M C
141 rdf:type schema:Person
142 Na7b79a9d43774331a175c1675524aca4 schema:name LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Kenneth_Anderson@dfci.harvard.edu.
143 rdf:type schema:Organization
144 Naa63a9e77a684032a706546aeea2ba5d rdf:first N9f5d7d6091ef497dbbc1f4f206734db9
145 rdf:rest N083fae36b93d42f5bd5b37a1a688540a
146 Nae4d16eb26a443c38cfadb8e3fc3025f schema:affiliation N66bbf36970e749a69cf8a20507aa4623
147 schema:familyName Li
148 schema:givenName Deyao
149 rdf:type schema:Person
150 Nb183176c14d14a9cba1653b64a682d2f schema:affiliation N7071e650580845059d232ccb5877d99e
151 schema:familyName Chauhan
152 schema:givenName Dharminder
153 rdf:type schema:Person
154 Nb6387fdc91654452bf806527f4dce9c2 schema:name dimensions_id
155 schema:value pub.1113300798
156 rdf:type schema:PropertyValue
157 Nc19a6ed256b14df2b0804db1b107e631 schema:affiliation N1b9a5231971148f2a87ca386d825cfec
158 schema:familyName Wimalasena
159 schema:givenName Virangika K
160 rdf:type schema:Person
161 Nc73ddfb8ee3a426ea2e9df07374e08ee schema:name LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
162 rdf:type schema:Organization
163 Nd1177a005f8a4b68bace344052cbc3da schema:affiliation N5c259e6ef87e4b79ba46f3f94e01a713
164 schema:familyName Wu
165 schema:givenName Lei
166 rdf:type schema:Person
167 Ne9c0858cb34142459e736bba4237bbdd schema:affiliation https://www.grid.ac/institutes/grid.4991.5
168 schema:familyName Filippakopoulos
169 schema:givenName Panagis
170 rdf:type schema:Person
171 Nf080bb2578cb4f3ca15016f3834c9748 schema:name Springer Nature - SN SciGraph project
172 rdf:type schema:Organization
173 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
174 schema:name Medical and Health Sciences
175 rdf:type schema:DefinedTerm
176 anzsrc-for:1112 schema:inDefinedTermSet anzsrc-for:
177 schema:name Oncology and Carcinogenesis
178 rdf:type schema:DefinedTerm
179 sg:grant.2440198 http://pending.schema.org/fundedItem sg:pub.10.1038/s41375-019-0467-z
180 rdf:type schema:MonetaryGrant
181 sg:grant.2470343 http://pending.schema.org/fundedItem sg:pub.10.1038/s41375-019-0467-z
182 rdf:type schema:MonetaryGrant
183 sg:grant.5476699 http://pending.schema.org/fundedItem sg:pub.10.1038/s41375-019-0467-z
184 rdf:type schema:MonetaryGrant
185 sg:journal.1097065 schema:issn 0887-6924
186 1476-5551
187 schema:name Leukemia
188 rdf:type schema:Periodical
189 sg:pub.10.1038/leu.2016.97 schema:sameAs https://app.dimensions.ai/details/publication/pub.1006372404
190 https://doi.org/10.1038/leu.2016.97
191 rdf:type schema:CreativeWork
192 sg:pub.10.1038/nature02263 schema:sameAs https://app.dimensions.ai/details/publication/pub.1012758273
193 https://doi.org/10.1038/nature02263
194 rdf:type schema:CreativeWork
195 sg:pub.10.1038/nature06924 schema:sameAs https://app.dimensions.ai/details/publication/pub.1052385095
196 https://doi.org/10.1038/nature06924
197 rdf:type schema:CreativeWork
198 sg:pub.10.1038/ncomms15540 schema:sameAs https://app.dimensions.ai/details/publication/pub.1085942910
199 https://doi.org/10.1038/ncomms15540
200 rdf:type schema:CreativeWork
201 sg:pub.10.1038/nrc1361 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033550220
202 https://doi.org/10.1038/nrc1361
203 rdf:type schema:CreativeWork
204 sg:pub.10.1038/s41589-018-0055-y schema:sameAs https://app.dimensions.ai/details/publication/pub.1104478464
205 https://doi.org/10.1038/s41589-018-0055-y
206 rdf:type schema:CreativeWork
207 sg:pub.10.1038/sj.cdd.4401702 schema:sameAs https://app.dimensions.ai/details/publication/pub.1045451673
208 https://doi.org/10.1038/sj.cdd.4401702
209 rdf:type schema:CreativeWork
210 https://app.dimensions.ai/details/publication/pub.1082860421 schema:CreativeWork
211 https://doi.org/10.1002/anie.201503720 schema:sameAs https://app.dimensions.ai/details/publication/pub.1039261715
212 rdf:type schema:CreativeWork
213 https://doi.org/10.1002/anie.201507978 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033234985
214 rdf:type schema:CreativeWork
215 https://doi.org/10.1002/gcc.20592 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033758484
216 rdf:type schema:CreativeWork
217 https://doi.org/10.1002/gcc.22262 schema:sameAs https://app.dimensions.ai/details/publication/pub.1009908512
218 rdf:type schema:CreativeWork
219 https://doi.org/10.1016/b978-0-12-407704-1.00005-1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003257664
220 rdf:type schema:CreativeWork
221 https://doi.org/10.1016/j.cbpa.2017.05.016 schema:sameAs https://app.dimensions.ai/details/publication/pub.1085961097
222 rdf:type schema:CreativeWork
223 https://doi.org/10.1016/j.ccr.2005.10.013 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030150234
224 rdf:type schema:CreativeWork
225 https://doi.org/10.1016/j.ccr.2009.08.019 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033289074
226 rdf:type schema:CreativeWork
227 https://doi.org/10.1016/j.ccr.2012.08.007 schema:sameAs https://app.dimensions.ai/details/publication/pub.1035292014
228 rdf:type schema:CreativeWork
229 https://doi.org/10.1016/j.ccr.2013.11.001 schema:sameAs https://app.dimensions.ai/details/publication/pub.1023348529
230 rdf:type schema:CreativeWork
231 https://doi.org/10.1016/j.chembiol.2015.05.009 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038118204
232 rdf:type schema:CreativeWork
233 https://doi.org/10.1016/j.chembiol.2017.05.024 schema:sameAs https://app.dimensions.ai/details/publication/pub.1086124525
234 rdf:type schema:CreativeWork
235 https://doi.org/10.1016/j.chembiol.2017.09.009 schema:sameAs https://app.dimensions.ai/details/publication/pub.1092620849
236 rdf:type schema:CreativeWork
237 https://doi.org/10.1016/j.molcel.2015.02.025 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010589854
238 rdf:type schema:CreativeWork
239 https://doi.org/10.1016/j.sbi.2016.01.004 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008904823
240 rdf:type schema:CreativeWork
241 https://doi.org/10.1021/acsomega.8b01479 schema:sameAs https://app.dimensions.ai/details/publication/pub.1107253733
242 rdf:type schema:CreativeWork
243 https://doi.org/10.1021/jacs.5b02069 schema:sameAs https://app.dimensions.ai/details/publication/pub.1025221893
244 rdf:type schema:CreativeWork
245 https://doi.org/10.1056/nejmoa030288 schema:sameAs https://app.dimensions.ai/details/publication/pub.1028177288
246 rdf:type schema:CreativeWork
247 https://doi.org/10.1073/pnas.141230798 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010028896
248 rdf:type schema:CreativeWork
249 https://doi.org/10.1080/14656566.2018.1528229 schema:sameAs https://app.dimensions.ai/details/publication/pub.1109831867
250 rdf:type schema:CreativeWork
251 https://doi.org/10.1093/hmg/ddi312 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001185591
252 rdf:type schema:CreativeWork
253 https://doi.org/10.1126/science.1177319 schema:sameAs https://app.dimensions.ai/details/publication/pub.1044064445
254 rdf:type schema:CreativeWork
255 https://doi.org/10.1126/science.1244917 schema:sameAs https://app.dimensions.ai/details/publication/pub.1012224724
256 rdf:type schema:CreativeWork
257 https://doi.org/10.1126/science.aab1433 schema:sameAs https://app.dimensions.ai/details/publication/pub.1019990583
258 rdf:type schema:CreativeWork
259 https://doi.org/10.1136/gut.2007.143065 schema:sameAs https://app.dimensions.ai/details/publication/pub.1015712242
260 rdf:type schema:CreativeWork
261 https://doi.org/10.1146/annurev-biochem-051810-094654 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017846425
262 rdf:type schema:CreativeWork
263 https://doi.org/10.1146/annurev.pharmtox.45.120403.100037 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033899181
264 rdf:type schema:CreativeWork
265 https://doi.org/10.1158/1078-0432.ccr-12-3752 schema:sameAs https://app.dimensions.ai/details/publication/pub.1000439946
266 rdf:type schema:CreativeWork
267 https://doi.org/10.1158/1535-7163.mct-04-0338 schema:sameAs https://app.dimensions.ai/details/publication/pub.1007689239
268 rdf:type schema:CreativeWork
269 https://doi.org/10.1182/blood-2005-03-1173 schema:sameAs https://app.dimensions.ai/details/publication/pub.1050947392
270 rdf:type schema:CreativeWork
271 https://doi.org/10.1182/blood-2012-01-401794 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014314116
272 rdf:type schema:CreativeWork
273 https://doi.org/10.1634/theoncologist.8-6-508 schema:sameAs https://app.dimensions.ai/details/publication/pub.1044258202
274 rdf:type schema:CreativeWork
275 https://doi.org/10.3892/or_00000368 schema:sameAs https://app.dimensions.ai/details/publication/pub.1071537173
276 rdf:type schema:CreativeWork
277 https://doi.org/10.6004/jnccn.2013.0199 schema:sameAs https://app.dimensions.ai/details/publication/pub.1078734503
278 rdf:type schema:CreativeWork
279 https://www.grid.ac/institutes/grid.4991.5 schema:alternateName University of Oxford
280 schema:name University of Oxford, Oxford, UK.
281 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...