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Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.
Abt, Evan R; Rosser, Ethan W; Durst, Matthew A; Lok, Vincent; Poddar, Soumya; Le, Thuc M; Cho, Arthur; Kim, Woosuk; Wei, Liu; Song, Janet; Capri, Joseph R; Xu, Shili; Wu, Nanping; Slavik, Roger; Jung, Michael E; Damoiseaux, Robert; Czernin, Johannes; Donahue, Timothy R; Lavie, Arnon; Radu, Caius G.
Afiliação
  • Abt ER; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Rosser EW; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, USA.
  • Durst MA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA; The Jesse Brown VA Medical Center, Chicago, IL, USA.
  • Lok V; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Poddar S; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Le TM; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Cho A; Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, South Korea.
  • Kim W; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Wei L; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Song J; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Capri JR; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Xu S; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
  • Wu N; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
  • Slavik R; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Jung ME; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, USA.
  • Damoiseaux R; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA, USA.
  • Czernin J; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Donahue TR; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA; David
  • Lavie A; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA; The Jesse Brown VA Medical Center, Chicago, IL, USA.
  • Radu CG; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: cradu@mednet.ucla.edu.
Cell Chem Biol ; 27(2): 197-205.e6, 2020 02 20.
Article em En | MEDLINE | ID: mdl-31734178
ABSTRACT
Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity. The JNK inhibitor JNK-IN-8 was found to potently inhibit nucleoside transport and engage ENT1. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant de novo pathway enzyme DHODH and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Nucleosídeos de Pirimidina / Transportador Equilibrativo 1 de Nucleosídeo / Oxirredutases atuantes sobre Doadores de Grupo CH-CH / Inibidores de Proteínas Quinases Idioma: En Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Nucleosídeos de Pirimidina / Transportador Equilibrativo 1 de Nucleosídeo / Oxirredutases atuantes sobre Doadores de Grupo CH-CH / Inibidores de Proteínas Quinases Idioma: En Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos