Recent advances of human dihydroorotate dehydrogenase inhibitors for cancer therapy: Current development and future perspectives

Zhang, Lele; Zhang, Jifa; Wang, Jiaxing; Ren, Changyu; Tang, Pan; Ouyang, Liang; Wang, Yuxi

doi:10.1016/j.ejmech.2022.114176

Cited by 29 publications

(20 citation statements)

References 128 publications

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“…Therefore, hDHODH inhibitors can be used to alleviate autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) caused by T lymphocytes related to autoimmunity (Bar‐Or et al, 2014; Breedveld & Dayer, 2000). Moreover, hDHODH has long been regarded as a promising target for cancer therapy, closely associated with various cancers such as melanoma, myeloma, AML, breast cancer, and small cell lung cancer, and plays an important role in oncogene reprogramming (Madak et al, 2019; Zhang et al, 2022). In addition, inhibiting hDHODH in viral host cells can reduce pyrimidine synthesis during viral replication, thereby realizing antiviral therapy, including the emerging coronavirus SARS‐CoV‐2 (Zheng et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…The only hDHODH inhibitors approved by the FDA currently are leflunomide and its active metabolite A771726 (teriflunomide) (Jones et al, 2021; Zhang et al, 2022), the former approved for the treatment of RA (Goldenberg, 1999), and the latter for MS (English & Aloi, 2015). However, these two drugs have side effects such as hepatotoxicity induced by mitochondrial dysfunction (Jones et al, 2021) and teratogenicity (Fukushima et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…These hDHODH inhibitors are classified according to different chemical scaffolds: quinoline derivatives including 4‐quinoline carboxylic acids; azole compounds including thiazoles, pyrazoles, indazoles/tetrahydroindazoles, benzimidazoles, and so on; indole derivatives; amide derivatives; anthranilate derivatives or 2‐amino nicotinic acid derivatives; benzoquinone‐bearing compounds; coumarin compounds; Schiff base compounds; etc. (Madak et al, 2019; Munier‐Lehmann et al, 2013; Zhang et al, 2022). In fact, the chemical structures of most hDHODH inhibitors are diverse and unique, and there is no obvious structural similarity between hDHODH inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase

Cao

et al. 2023

Chem Biol Drug Des

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Human dihydroorotate dehydrogenase (hDHODH) is a promising drug target for many diseases including autoimmune diseases, cancer, and viral infection. To develop more novel and potent hDHODH inhibitors, we screened our in-house library of old drugs. We found that tiratricol (3,3′,5-triiodothyroacetic acid), a thyroid hormone metabolite, has potent hDHODH inhibitory activity (IC 50 : 0.754 ± 0.126 μM), and its precursor tetrac (3,3′,5,5′-tetraiodothyroacetic acid) also shows a certain inhibitory activity against hDHODH (IC 50 : 11.960 ± 1.453 μM).Enzyme kinetic analysis shows that tiratricol and tetrac are noncompetitive inhibitors versus CoQ 0 , which is different from the positive control A771726.ThermoFMN assay, molecular docking and site-directed mutagenesis all indicate that tiratricol and tetrac interact with more key residues of hDHODH than A771726, especially some hydrophobic residues in Subsite 1. In conclusion, our experiment results indicate a potential new use for the old drug, tiratricol, and provide a novel chemical scaffold for the design of hDHODH inhibitors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase

Cao

et al. 2023

Chem Biol Drug Des

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“…Targeting h DHODH is a quite complex matter being the target a mitochondrial enzyme: the inhibitors must be lipophilic (log D 7.4 2.5–3 range) in order to be able to transfer optimal activity at the enzymatic level to cellular efficacy, exposing them to solubility issues. Because of these issues, as can be observed from the recent literature, it is important to keep proposing new scaffolds as a source of optimized inhibitors. The SAR of MEDS433 has already been investigated identifying the biphenyl scaffold , as a source of effective interaction with the lipophilic h DHODH subsite 1.…”

Section: Introductionmentioning

confidence: 99%

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Aryloxyaryl Moiety

et al. 2022

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In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure–activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.

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“…Pyrimidine nucleotides assume a huge part in cell proliferation since pyrimidines are needed for the biosynthesis of RNA, DNA, phospholipids, and glycoproteins, and are connected by phosphodiester extensions to purine nucleotides in double-stranded DNA, both in mitochondria and nucleus 6 , 7 . So that the utility of inhibitors of the de novo nucleotide biosynthetic pathways, important for the proliferation of residing entities, provides therapeutic possibilities for the remedy of autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis and cancer 8 , 9 .…”

mentioning

confidence: 99%

Discovery of potential natural dihydroorotate dehydrogenase inhibitors and their synergism with brequinar via integrated molecular docking, dynamic simulations and in vitro approach

Khairy

Hammoda

Çeli̇k

et al. 2022

Sci Rep

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The critical function of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis attracted a great interest throughout beyond decades. Inhibitors of human DHODH (hDHODH) have validated efficacy for remedy of many immunological diseases. Brequinar and leflunomide are examples of such compounds. However, most of such immunosuppressive medications suffer from a lot of side effects and accompanied by adverse metabolic disturbances and toxicities. So that, immunomodulation utilizing natural products received the attention of many researchers. In this study, computer-aided molecular docking, molecular dynamic (MD) simulations and biochemical testing were utilized to find new pharmacologically active chemical entities from natural sources to combat immunosuppressive diseases. More specifically, Glide docking was used for a structure-based virtual screening of in-house 3D database of compounds retrieved from some traditionally known immunomodulatory plants surveyed from literature. The top five scored plants were found to be Zingiber officinale, Curcuma longa, Glycyrrhiza glabra, Allium sativum and Olea europaea. In vitro hDHODH inhibitory assays illustrated the ability of Allium sativum and silymarin standard hits; specifically, silibinin, to significantly inhibit the hDHODH enzyme. Molecular docking and MD simulations revealed a strong binding of the discovered hits within the active site. Following that, the most promising hits were tested separately with brequinar in a fixed-ratio combination setting to assess their combined effects on hDHODH catalytic inhibition. The binary combination of silibinin and brequinar revealed that in this combination, brequinar could be utilized at a dose 9.33-fold less when compared to its single-use to produce 99% inhibition for hDHODH enzyme. These findings confirmed that this binary mixture is an excellent combination providing better therapeutic effects and lower side effects.

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Recent advances of human dihydroorotate dehydrogenase inhibitors for cancer therapy: Current development and future perspectives

Cited by 29 publications

References 128 publications

Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase

Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Aryloxyaryl Moiety

Discovery of potential natural dihydroorotate dehydrogenase inhibitors and their synergism with brequinar via integrated molecular docking, dynamic simulations and in vitro approach

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