Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.,Cell Chemical Biology

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Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-11-13 , DOI: 10.1016/j.chembiol.2019.10.012
Evan R Abt ₁ , Ethan W Rosser ₂ , Matthew A Durst ₃ , Vincent Lok ₁ , Soumya Poddar ₁ , Thuc M Le ₁ , Arthur Cho ₄ , Woosuk Kim ₁ , Liu Wei ₁ , Janet Song ₁ , Joseph R Capri ₁ , Shili Xu ₅ , Nanping Wu ₅ , Roger Slavik ₁ , Michael E Jung ₆ , Robert Damoiseaux ₇ , Johannes Czernin ₁ , Timothy R Donahue ₈ , Arnon Lavie ₃ , Caius G Radu ₁

Affiliation

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.
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.
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA; The Jesse Brown VA Medical Center, Chicago, IL, USA.
Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, South Korea.
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.
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, USA.
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.
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.

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.

中文翻译：

代谢修饰剂筛选揭示了核苷酸代谢中蛋白质激酶抑制剂的次级靶标。

嘧啶核苷酸尿苷单磷酸酯（UMP）的生物合成对于细胞增殖至关重要，并且是通过从头聚合和挽救代谢途径的活性来实现的。在这里，我们报告开发和应用基于细胞的代谢修饰剂筛选平台，该平台利用嘧啶代谢中的冗余性来发现选择性UMP生物合成调节剂。在评估蛋白激酶抑制剂库中，我们鉴定了具有核苷酸代谢修饰活性的多种化合物。发现JNK抑制剂JNK-IN-8有效抑制核苷转运并与ENT1结合。

更新日期：2019-11-13

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