Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

Alamri, Raghad D; Elmeligy, Mazen A; Albalawi, Ghadeer A; Alquayr, Sarah M; Alsubhi, Samaher S; El-Ghaiesh, Sabah

doi:10.1016/j.intimp.2021.107398

Cited by 31 publications

(27 citation statements)

References 139 publications

(105 reference statements)

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“…DHODH inhibitors (DHODHi) have been used to treat malignant tumors, autoimmune diseases, viral or bacterial infections, parasitic diseases, and other diseases [ 23 , 31 , 33 , 34 , 35 ]. DHODHi inhibit viral infection by three mechanisms: (1) inhibiting viral replication (pathway 1 in Figure 2 ), (2) promoting interferon-stimulated genes (ISGs) expression (pathway 2 in Figure 2 ), and (3) regulating inflammation (pathway 3 in Figure 2 ).…”

Section: The Essential Role Of Dhodh In the De Novo ...mentioning

confidence: 99%

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

Song

et al. 2022

Viruses

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New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection.

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Section: The Essential Role Of Dhodh In the De Novo ...mentioning

confidence: 99%

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

Song

et al. 2022

Viruses

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“…Exogenous uridine (100 μM) supplementation significantly decreased the proliferation inhibitory rate to 3.3, 6.2, 17.1, and 21.3%, respectively, suggesting that exogenous uridine predominantly rescued proliferation inhibition induced by compound 13t . Furthermore, previous studies revealed that teriflunomide also exhibited inhibitory activities against several human protein kinases, such as EGFR, JAK1, and JAK3. − Therefore, we evaluated the inhibitory activities of 13t (10 μM) against 98 human protein kinases that are commonly activated in human malignancies including EGFR, JAK1, and JAK3. The results showed that 13t at a high concentration of 10 μM only affected the protein kinases activity very slightly with most of the inhibitory rate lower than 30% (Table S1), suggesting that 13t did not affect the kinases activity.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment

Yang

Luo

et al. 2021

J. Med. Chem.

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Human dihydroorotate dehydrogenase (hDHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

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“…Lef is a malononitrile derivative that inhibits dihydroorotate dehydrogenase and several protein tyrosine kinases [ 43 , 44 ]. Although Lef is an immunomodulatory agent used to treat rheumatoid arthritis [ 45 ], there have been no studies on the effects of Lef on osteoblastic differentiation. Malviya et al reported that 15 µM Lef inhibited the proliferation of primary human osteoblasts [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Cell-Based Double-Screening Method to Identify a Reliable Candidate for Osteogenesis-Targeting Compounds

et al. 2022

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Small-molecule compounds strongly affecting osteogenesis can form the basis of effective therapeutic strategies in bone regenerative medicine. A cell-based high-throughput screening system might be a powerful tool for identifying osteoblast-targeting candidates; however, this approach is generally limited with using only one molecule as a cell-based sensor that does not always reflect the activation of the osteogenic phenotype. In the present study, we used the MC3T3-E1 cell line stably transfected with the green fluorescent protein (GFP) reporter gene driven by a fragment of type I collagen promoter (Col-1a1GFP-MC3T3-E1) to evaluate a double-screening system to identify osteogenic inducible compounds using a combination of a cell-based reporter assay and detection of alkaline phosphatase (ALP) activity. Col-1a1GFP-MC3T3-E1 cells were cultured in an osteogenic induction medium after library screening of 1280 pharmacologically active compounds (Lopack1280). After 7 days, GFP fluorescence was measured using a microplate reader. After 14 days of osteogenic induction, the cells were stained with ALP. Library screening using the Col-1a1/GFP reporter and ALP staining assay detected three candidates with significant osteogenic induction ability. Furthermore, leflunomide, one of the three detected candidates, significantly promoted new bone formation in vivo. Therefore, this double-screening method could identify candidates for osteogenesis-targeting compounds more reliably than conventional methods.

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Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

Cited by 31 publications

References 139 publications

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment

Cell-Based Double-Screening Method to Identify a Reliable Candidate for Osteogenesis-Targeting Compounds

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