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

25 Pages Posted: 19 May 2019 Sneak Peek Status: Under Review

See all articles by Evan R. Abt

Evan R. Abt

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Ethan W. Rosser

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division; University of California, Los Angeles (UCLA) - Department of Chemistry and Biochemistry

Matthew A. Durst

University of Illinois at Chicago - Department of Biochemistry and Molecular Genetics; Jesse Brown Veterans Affairs Medical Center

Soumya Poddar

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Vincent Lok

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Liu Wei

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Woosuk Kim

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Janet Song

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Joseph R. Capri

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Thuc M. Le

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Roger Slavik

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Michael E. Jung

University of California, Los Angeles (UCLA) - Department of Chemistry and Biochemistry

Robert Damoiseaux

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - California Nanosystems Institute

Johannes Czernin

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Timothy R. Donahue

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP); University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division; University of California, Los Angeles (UCLA) - Department of Surgery; University of California, Los Angeles (UCLA) - David Geffen School of Medicine; University of California, Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center

Arnon Lavie

University of Illinois at Chicago - Department of Biochemistry and Molecular Genetics; Jesse Brown Veterans Affairs Medical Center

Caius G. Radu

UCLA; University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

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Abstract

A cell-based metabolic modifier screening platform for the discovery of modulators of convergent pyrimidine nucleotide biosynthetic pathways was designed and implemented. In screening a library of protein kinase inhibitors, multiple compounds were shown to possess previously uncharacterized nucleotide metabolism-modifying activity. The JNK inhibitor JNK-IN-8 was found to be a potent inhibitor of nucleoside transport, a property which was confirmed using nucleoside-analog Positron Emission Tomography (PET) imaging in mice. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant enzyme dihydroorotate dehydrogenase (DHODH) and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH.

Keywords: Pyrimidine metabolism, cancer metabolism, phenotypic screening, target identification

Suggested Citation

Abt, Evan R. and Rosser, Ethan W. and Durst, Matthew A. and Poddar, Soumya and Lok, Vincent and Wei, Liu and Kim, Woosuk and Song, Janet and Capri, Joseph R. and Le, Thuc M. and Slavik, Roger and Jung, Michael E. and Damoiseaux, Robert and Czernin, Johannes and Donahue, Timothy R. and Lavie, Arnon and Radu, Caius G., Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism (May 17, 2019). CELL-CHEMICAL-BIOLOGY-D-19-00156. Available at SSRN: https://ssrn.com/abstract=3389530 or http://dx.doi.org/10.2139/ssrn.3389530
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Evan R. Abt

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

Ethan W. Rosser

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

University of California, Los Angeles (UCLA) - Department of Chemistry and Biochemistry ( email )

Los Angeles, CA 90095
United States

Matthew A. Durst

University of Illinois at Chicago - Department of Biochemistry and Molecular Genetics ( email )

1200 W Harrison St
Chicago, IL 60607
United States

Jesse Brown Veterans Affairs Medical Center ( email )

Chicago, IL
United States

Soumya Poddar

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

Vincent Lok

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

Liu Wei

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Los Angeles, CA
United States

Woosuk Kim

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

Janet Song

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Los Angeles, CA
United States

Joseph R. Capri

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

Thuc M. Le

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division

Los Angeles, CA
United States

Roger Slavik

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

Michael E. Jung

University of California, Los Angeles (UCLA) - Department of Chemistry and Biochemistry

Los Angeles, CA 90095
United States

Robert Damoiseaux

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - California Nanosystems Institute ( email )

570 Westwood Plaza
Building 114
Los Angeles, CA 90095
United States

Johannes Czernin

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

Timothy R. Donahue

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP) ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

University of California, Los Angeles (UCLA) - Department of Surgery ( email )

Los Angeles, CA
United States

University of California, Los Angeles (UCLA) - David Geffen School of Medicine ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

University of California, Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center ( email )

10833 Le Conte Avenue
Los Angeles, CA 90095-6939
United States

Arnon Lavie

University of Illinois at Chicago - Department of Biochemistry and Molecular Genetics ( email )

1200 W Harrison St
Chicago, IL 60607
United States

Jesse Brown Veterans Affairs Medical Center ( email )

Chicago, IL
United States

Caius G. Radu (Contact Author)

UCLA ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States
3108251205 (Phone)
3108251205 (Fax)

University of California, Los Angeles (UCLA) - Ahmanson Translational Imaging Division ( email )

Los Angeles, CA
United States

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