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; Cho, Arthur; Kim, Woosuk; Liu, Wei; Song, Janet; Capri, Joseph; Xu, Shili; Wu, Nanping; Slavik, Roger; Jung, Michael E.; Damoiseaux, Robert; Czernin, Johannes; Donahue, Timothy R.; Lavie, A.; Radu, Caius G.

doi:10.1016/j.chembiol.2019.10.012

Cited by 19 publications

(16 citation statements)

References 58 publications

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“…Until now, many DHODH inhibitors with different structures have been reported [ 7 ], such as canonical DHODH inhibitors BRQ [ 125 ], leflunomide [ 2 ], teriflunomide [ 126 ], ALASN003 [ 127 ], BAY2202234 [ 43 ], and other novel inhibitors which show DHODH inhibition effects including viral growth inhibitory factor [ 128 ], PARP inhibitor [ 129 ], myeloid differentiation inducing agent [ 60 ], p53 activating factor [ 61 ], a natural product isobavachalcone [ 70 ], or vascular endothelial growth factor A (VEGF-A) mRNA translation inhibitor [ 40 ]. Over 90 patent applications involving DHODH inhibitors have been filed in the last decade [ 107 , 130 ]. Notably, there is only one product, ASLAN003, that has been awarded orphan drug designation from the Food and Drug Administration (FDA) up to now [ 131 ].…”

Section: Dhodh Inhibitorsmentioning

confidence: 99%

“…In recent years, novel DHODH inhibitors are massively emerging, which include analogs of BRQ [ 60 , 102 ], IMU-838, and its active metabolite vidofludimus [ 152 – 154 ], PTC299 [ 40 , 155 ], DD264 [ 128 ], plant extract Celastrol [ 156 ], protein kinase inhibitors OSU-03012 and TAK-632 [ 112 , 130 , 157 ], isobavachalcone [ 70 ], tetrahydroindazole (HZ) analogs [ 35 , 61 ], alkaloid cerpegin-related P1788 [ 158 ], compound 11 [ 79 ], etc. (Table 3 ).…”

Section: Dhodh Inhibitorsmentioning

confidence: 99%

“…Notably, OSU-03012 and TAK-632 bind in the same hydrophobic tunnel of DHODH as known inhibitors BRQ and teriflunomide. By competitively inhibiting the binding of ubiquinone, these compounds prevent DHODH from completing its redox cycle and effectively abrogate its activity [ 130 ]. Meanwhile, OSU-03012 and analogs can inhibit pyrimidine biosynthesis in host cells to inhibit viral replication, specifically illustrating regulation of DHODH activity [ 112 , 130 ].…”

Section: Dhodh Inhibitorsmentioning

confidence: 99%

“…Given that p53 is generally mutated in more than 50% of tumors, the simultaneous inactivation of DHODH and Chk1 kinase is a potential method for the treatment of refractory p53 mutant tumors [ 37 ]. As salvage and de novo pyrimidine pathways are suppressed by ATR blockade [ 157 ], combination of ATR inhibitor and OSU-03012, a DHODH inhibitor, reveals synergy against pancreatic ductal adenocarcinoma [ 130 ]. These observations suggested that DHODH inhibitors may have utility in conjunction with DNA damage response pathway inhibitors [ 130 , 157 ].…”

Section: Prospects Of Dhodh Inhibitors In Cancer Therapymentioning

confidence: 99%

“…As salvage and de novo pyrimidine pathways are suppressed by ATR blockade [ 157 ], combination of ATR inhibitor and OSU-03012, a DHODH inhibitor, reveals synergy against pancreatic ductal adenocarcinoma [ 130 ]. These observations suggested that DHODH inhibitors may have utility in conjunction with DNA damage response pathway inhibitors [ 130 , 157 ]. Meanwhile, in case of DHODH inhibitors ineffective due to efficient uridine salvage synthesis in certain cells, combination DHODH inhibitors with non-competitive pyrimidine salvage enzyme uridine-cytidine kinase 2 (UCK2) inhibitors was able to suppress nucleoside synthesis and inhibit cell proliferation [ 166 ].…”

Section: Prospects Of Dhodh Inhibitors In Cancer Therapymentioning

confidence: 99%

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DHODH and cancer: promising prospects to be explored

et al. 2021

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Human dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy. In this review, we mainly unravel the biological function of DHODH in tumor progression, including its crucial role in de novo pyrimidine synthesis and mitochondrial respiratory chain in cancer cells. Moreover, various DHODH inhibitors developing in the past decades are also been displayed, and the specific mechanism between DHODH and its additional effects are illustrated. Collectively, we detailly discuss the association between DHODH and tumors in recent years here, and believe it will provide significant evidences and potential strategies for utilizing DHODH as a potential target in preclinical and clinical cancer therapies.

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Section: Dhodh Inhibitorsmentioning

confidence: 99%

Section: Dhodh Inhibitorsmentioning

confidence: 99%

Section: Dhodh Inhibitorsmentioning

confidence: 99%

Section: Prospects Of Dhodh Inhibitors In Cancer Therapymentioning

confidence: 99%

Section: Prospects Of Dhodh Inhibitors In Cancer Therapymentioning

confidence: 99%

See 3 more Smart Citations

DHODH and cancer: promising prospects to be explored

et al. 2021

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Synthesis and biological evaluation of new quinoline‐4‐carboxylic acid‐chalcone hybrids as dihydroorotate dehydrogenase inhibitors

Petrović

Roschger

Lang

et al. 2022

Archiv der Pharmazie

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Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen-Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC 50 values ranging from 0.12 to 0.58 μM.The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC 50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD 7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties. K E Y W O R D S chalcones, dihydroorotate dehydrogenase, hDHODH inhibitors, quinoline-4-carboxylic acid 1 | INTRODUCTION Dihydroorotate dehydrogenase (DHODH) is located in the inner mitochondrial membrane and represents one of the most important flavin-dependent enzymes, playing a significant role in the de novo biosynthesis of pyrimidine nucleotides. The fourth step of this biosynthesis pathway is catalyzed by DHODH, a rate-limitingenzyme responsible for the oxidation of dihydroorotate to orotate. [1] Considering the importance of pyrimidine nucleotides for cellular metabolism, especially in tumor cell proliferation and their requirement for the biosynthesis of macromolecules such as DNA, RNA, phospholipids, and glycoproteins, inhibition of this enzyme has gained a lot of attention in recent decades. [2] Furthermore, DHODH was noted as an ideal target for the treatment of various diseases and these facts encouraged many scientists to design novel inhibitors that will disrupt the function of the enzyme consequently causing the deficiency of essential pyrimidine nucleotides. Accordingly, a variety of specific inhibitors with a wide range of heterocyclic scaffolds and diverse

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Mechanical abrasion stimulation: Altered epidermal mucus composition and microbial community in grass carp (Ctenopharyngodon idella)

Wang,

Fei,

Gao

et al. 2024

Aquaculture Reports

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

Abstract: Highlights d Convergent UMP biosynthetic pathways interchangeably sustain cancer cell proliferation d Phenotypic screens can identify selective modulators of convergent metabolic networks d Multiple protein kinase inhibitors possess secondary targets within UMP metabolism

Cited by 19 publications

References 58 publications

DHODH and cancer: promising prospects to be explored

DHODH and cancer: promising prospects to be explored

Synthesis and biological evaluation of new quinoline‐4‐carboxylic acid‐chalcone hybrids as dihydroorotate dehydrogenase inhibitors

Mechanical abrasion stimulation: Altered epidermal mucus composition and microbial community in grass carp (Ctenopharyngodon idella)

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