Dual Binding Mode of a Novel Series of DHODH Inhibitors

Baumgartner, Roland; Walloschek, Markus; Kralik, Martin; Gotschlich, Astrid; Tasler, Stefan; Mies, Jan; Leban, Johann

doi:10.1021/jm0506975

Cited by 95 publications

(127 citation statements)

References 36 publications

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“…2C) (20). Interestingly, both enzymes belong to a common pathway, the de novo pyrimidine biosynthesis pathway (21).…”

Section: Resultsmentioning

confidence: 99%

“…The protein identified by 6b was dihydroorotate dehydrogenase (DHODH) (19), and that of 14b was the multifunctional polypeptide termed CAD (20) [comprising the catalytic triad carbamoyl phosphatase (CSPase), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase)]. CAD initiates and regulates de novo pyrimidine biosynthesis, delivering dihydroorotate to DHODH, the fourth and rate-limiting enzyme in the de novo pathway (21). Together, both lead to the production of uridine that serves as an activated precursor of RNA and DNA, CDP-diacylglycerol phosphoglyceride, and UDP sugars for protein glycosylation/ glycogen synthesis (28).…”

Section: Discussionmentioning

confidence: 99%

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Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

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“…2C) (20). Interestingly, both enzymes belong to a common pathway, the de novo pyrimidine biosynthesis pathway (21).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In pyrimidine biosynthesis, the rate limiting step has been described as CPSII (the first enzyme of CAD) (11) and dihydroorotate dehydrogenase (DHODH) (136), the fourth step in the pathway (Figure 2), again implying distributed flux control. This and the fact that several enzymes in both purine and pyrimidine biosynthesis have activities residing on a single polypeptide chain indicates a level of coordinate, stoichiometric expression and the possibility of channeling intermediates from one enzyme to another (see next section).…”

Section: Nucleic Acid Synthesis: Energetics and Nutrient Requirementsmentioning

confidence: 99%

Regulation of mammalian nucleotide metabolism and biosynthesis

Lane

Fan

2015

Nucleic Acids Research

722

631

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Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.

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“…Overall, the crystal structure is similar to several other reported structures of DHODH bound to small-molecule inhibitors, the interaction with Arg136 being the most important interaction. 24,25 The X-ray structure indicates that binding to the enzyme may be increased by modifying ML390 with a ring in its central portion to lock the molecule into its binding conformation with the amide substituents cis about the ring. Synthesis of such compounds was unsuccessful, and furthermore, solutions of ML390 did show some decomposition over time.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia

Lewis

Sykes

Law

et al. 2016

ACS Med. Chem. Lett.

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Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.

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Dual Binding Mode of a Novel Series of DHODH Inhibitors

Cited by 95 publications

References 36 publications

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Regulation of mammalian nucleotide metabolism and biosynthesis

Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia

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