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Immunomodulating Agents in Gastrointestinal Disease
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Samir A. Shah, Athos Bousvaros, A. Christopher Stevens
Like MMF, brequinar sodium (BQR) interferes with DNA synthesis and T and B cell proliferation. It inhibits the enzyme dihydroorotate dehydrogenase, which is essential in the de novo synthesis of pyrimidines in the lymphocyte. Brequinar sodium decreases DNA and ribonucleic acid (RNA) synthesis, lymphocyte proliferation, and cytokine and antibody production. In vivo transplantation experiments in rat and monkey animal models demonstrate that brequinar decreases proinflamma-tory cytokine messenger RNA (mRNA) in allografts and prolongs cardiac and liver allograft survival [189–191].
In vitro metabolism, pharmacokinetics and drug interaction potentials of emvododstat, a DHODH inhibitor
Published in Xenobiotica, 2022
Jiyuan Ma, Diksha Kaushik, Shirley Yeh, Valerie Northcutt, John Babiak, Nicole Risher, Marla Weetall, Young-Choon Moon, Ellen M. Welch, Lachlan Molony, Kylie O’Keefe, Ronald Kong
It was later demonstrated that the mechanism of action of emvododstat is due to its direct and potent inhibition of the dihydroorotate dehydrogenase (DHODH) enzyme, a rate-limiting enzyme in de novo pyrimidine nucleotide synthesis. Inhibition of VEGFA production by emvododstat is a downstream effect of inhibiting de novo pyrimidine synthesis as it can be completely rescued by exogenously added uridine (Cao et al. 2019). Subsequent studies using cell lines of a broad array of solid tumour and haematologic malignancies indicated that emvododstat is more potent against leukaemic malignancies, including acute myeloid leukaemia (AML), than against solid tumours. In the most recent work, emvododstat has shown broad-spectrum antiviral activity and particularly potently inhibited viral replication and suppressed induction of inflammatory cytokines in SARS-CoV-2 cell-based assays (Luban et al. 2021). Thus, emvododstat has the potential to address unmet needs in certain cancers and RNA viral infections where the cancer cells or viruses rely on the de novo biosynthesis of pyrimidine nucleotides for survival or rapid proliferation. Currently emvododstat is under clinical development for the treatment of AML and COVID-19 (coronavirus SARS-CoV-2).
Assessing the risk of multiple sclerosis disease-modifying therapies
Published in Expert Review of Neurotherapeutics, 2019
Xavier Ayrignac, Philippe-Antoine Bilodeau, Alexandre Prat, Marc Girard, Pierre Labauge, Jacques Le Lorier, Catherine Larochelle, Pierre Duquette
Teriflunomide is an active metabolite of leflunomide, used for rheumatoid arthritis. It is believed to selectively inhibit the proliferation of autoreactive B- and T-lymphocytes by the inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) which is essential for de novo pyrimidine synthesis. During phase III RCTs, the incidence of infections (including serious infections) was similar on placebo and on teriflunomide 14 mg; rare opportunistic infections (gastrointestinal TB and CMV hepatitis) were seen in the TOWER trial [37–40]. Long term extensions of RCTs confirmed the absence of increased risk of infections, or opportunistic infections [41]. Herpes infections (usually mild) have been rarely described. One case of PML has been published in a patient on teriflunomide, but with previous prolonged exposure to natalizumab [42]. Moreover, PML has been rare with leflunomide. Altogether, it is not clear whether PML risk is increased under teriflunomide. Other AEs during RCTs included ALT increase, diarrhea, nausea, hair thinning (all > 10%), whereas high blood pressure and neuropathy were respectively seen in 5.3% and 1.9% [37–40]. Overall, in RCTs, AEs led to treatment discontinuation in 12.5% of patients, mainly because of increased ALT [37–39]. In real world studies; persistence at one to two years varies between 50% and 89% [43,44]. Between 53% and 89% of discontinuations are due to an AE, mostly diarrhea, hair thinning and ALT increase [43,44]. A single case of fatal severe toxic epidermal necrolysis has been reported with teriflunomide for less than 1 month and, more recently, a case of severe hypertriglyceridemia (>5000mg/dL) [45,46].
The emergence of dihydroorotate dehydrogenase (DHODH) as a therapeutic target in acute myeloid leukemia
Published in Expert Opinion on Therapeutic Targets, 2018
Dihydroorotate dehydrogenase (DHODH) is a ubiquitous enzyme located within the inner membrane of the mitochondria. Using the cofactor ubiquinone, DHODH catalyzes the fourth step of de novo pyrimidine synthesis: the conversion of dihydroorotate to orotate. DHODH is the only enzyme capable of performing this conversion and it is therefore essential for the cell’s ability to produce uridine monophosphate (Figure 1).