Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.

Binding Sites Cell Line, Tumor Cell Survival / drug effects Crystallography, X-Ray Dihydroorotate Dehydrogenase Drug Design Equilibrative Nucleoside Transporter 1 / antagonists & inhibitors Humans Molecular Dynamics Simulation Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors Protein Kinase Inhibitors / chemistry Pyrimidine Nucleosides / metabolism Small Molecule Libraries / chemistry
cancer metabolism phenotypic screening pyrimidine metabolism target identification

Journal

Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030

Informations de publication

Date de publication:
20 02 2020
Historique:
received: 01 05 2019
revised: 30 08 2019
accepted: 25 10 2019
pubmed: 18 11 2019
medline: 14 5 2021
entrez: 18 11 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.chembiol.2019.10.012 PMID: 31734178 PMC: PMC7035983
pubmed: 31734178
pii: S2451-9456(19)30357-5
doi: 10.1016/j.chembiol.2019.10.012
pmc: PMC7035983
mid: NIHMS1543678
pii:
doi:

Substances chimiques

Dihydroorotate Dehydrogenase 0
Equilibrative Nucleoside Transporter 1 0
Protein Kinase Inhibitors 0
Pyrimidine Nucleosides 0
Small Molecule Libraries 0
Oxidoreductases Acting on CH-CH Group Donors EC 1.3.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

197-205.e6

Subventions

Organisme : BLRD VA
ID : I01 BX001919
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA187678
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009120
Pays : United States

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests C.G.R. and J.C. are co-founders of Sofie Biosciences and Trethera Corporation. M.E.J. is a co-founder of Trethera Corporation. They and the University of California (UC) hold equity in Sofie Biosciences and Trethera Corporation. The intellectual property developed by C.G.R., J.C., and M.E.J. and licensed by UC to Sofie Biosciences and Trethera Corporation was not used in this study.

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Auteurs

Evan R 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.

Ethan W 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.

Matthew A 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.

Vincent 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.

Soumya 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.

Thuc M 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.

Arthur Cho (A)

Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, South Korea.

Woosuk 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.

Liu 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.

Janet 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.

Joseph R 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.

Shili 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.

Nanping 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.

Roger 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.

Michael E Jung (ME)

Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, USA.

Robert 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.

Johannes 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.

Timothy R 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 Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.

Arnon 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.

Caius G 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.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Survie cellulaire › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-CH group donors › Dihydroorotate dehydrogenase › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs équilibrants de nucléosides › Transporteur équilibrant de nucléosides de type 1 › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-CH group donors › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Nucléosides pyrimidiques › Metabolic Modifier Screen Reveals Secondary...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Bibliothèques de petites molécules › Metabolic Modifier Screen Reveals Secondary...