4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

Fitzpatrick, Leo R.; Deml, Ludwig; Hofmann, Claudia; Small, Jeffrey S.; Groeppel, Manfred; Hamm, Svetlana; Lemstra, S.; Leban, Johann; Ammendola, Aldo

doi:10.1002/ibd.21264

Cited by 59 publications

(60 citation statements)

References 34 publications

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“…However, we showed previously that Vido inhibits IL-17 secretion by peripheral blood mononuclear cells (PBMCs) independently of its effects on cellular proliferation (Fitzpatrick et al, 2010a). Specifically, we found that the inhibitory effects of Vido on cellular proliferation could be reversed in the presence of exogenous uridine (Uri) (Fitzpatrick et al, 2010a). In contrast, Uri could not reverse the inhibitory effect of Vido on phytohemagglutinin-stimulated IL-17 secretion by PBMCs.…”

Section: Introductionmentioning

confidence: 89%

“…Because of its capability to inhibit DHODH, Vido can inhibit leukocyte proliferation (Fitzpatrick et al, 2010a;Kulkarni et al, 2010). However, we showed previously that Vido inhibits IL-17 secretion by peripheral blood mononuclear cells (PBMCs) independently of its effects on cellular proliferation (Fitzpatrick et al, 2010a). Specifically, we found that the inhibitory effects of Vido on cellular proliferation could be reversed in the presence of exogenous uridine (Uri) (Fitzpatrick et al, 2010a).…”

Section: Introductionmentioning

confidence: 97%

“…In contrast, activated lymphocytes synthesize 4-to 8-fold more pyrimidines and use the de novo biosynthetic pathway (Rü ckemann et al, 1998;Fox et al, 1999). Because of its capability to inhibit DHODH, Vido can inhibit leukocyte proliferation (Fitzpatrick et al, 2010a;Kulkarni et al, 2010). However, we showed previously that Vido inhibits IL-17 secretion by peripheral blood mononuclear cells (PBMCs) independently of its effects on cellular proliferation (Fitzpatrick et al, 2010a).…”

Section: Introductionmentioning

confidence: 98%

“…Vido [2-(3-Fluoro-3'-methoxybiphenyl-4-ylcarbamoyl)-cyclopent-1-enecarboxylic acid (4SC-101)] is a potent inhibitor of dihydro-orotate dehydrogenase (DHODH), which is a key enzyme involved in pyrimidine biosynthesis (Fitzpatrick et al, 2010a;Kulkarni et al, 2010). Most mammalian cells recruit uridine by recycling through a salvage pathway.…”

Section: Introductionmentioning

confidence: 99%

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Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Fitzpatrick

Small

Doblhofer

et al. 2012

J Pharmacol Exp Ther

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Vidofludimus (Vido) is a novel oral immunomodulatory drug that inhibits dihydro-orotate dehydrogenase and lymphocyte proliferation in vitro. Vido inhibits interleukin (IL)-17 secretion in vitro independently of effects on lymphocyte proliferation. Our primary goal was to evaluate the in vivo effects of Vido on IL-17 secretion and the parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. To further delineate the mechanism of action for Vido, rats were dosed concomitantly with uridine (Uri). Young Wistar rats received a 150-l enema of either phosphate-buffered saline (PBS) or TNBS on study day 1. The ex vivo effects of Vido on 24-h colonic IL-17 secretion were determined by using colonic strips from PBS-or TNBStreated rats. Some rats were dosed with vehicle, Vido, or Vido ϩ Uri for 6 days. On day 6, the parameters of colitis were determined from colonic tissue. These parameters included macroscopic, histological, and transcription factor measurements, IL-17 production, and numbers of CD3 ϩ T cells. Ex vivo Vido completely blocked IL-23 ϩ IL-1␤-stimulated secretion of IL-17 by colonic strips. In vivo Vido treatment alone most effectively reduced macroscopic and histological pathology and the numbers of CD3 ϩ T cells. In contrast, similarly reduced nuclear signal transducer and activator of transcription 3 (STAT3) binding and IL-17 levels were observed from animals treated with Vido alone and Vido ϩ Uri. Vido improves TNBS-induced colonic inflammation by a unique dual mode of action: 1) inhibiting expansion of colonic T lymphocytes, and 2) suppressing colonic IL-17 production, which is independent from the control of T-lymphocyte proliferation, by inhibition of STAT3 and nuclear factor-B activation.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Fitzpatrick

Small

Doblhofer

et al. 2012

J Pharmacol Exp Ther

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“…Although some studies have shown that antibody depletion of IL-17 increases the severity of acute colitis in mice (250), other mouse experiments conversely demonstrated that IL-17 receptor (IL-17R) deficiency reduces colitis severity (251). Novel drugs that block IL-17 activity have also been shown to confer protection in models of chronic colitis (252,253). Thus, there is currently much evidence to suggest a critical role for Th17 cells and their associated cytokines in UC pathogenesis.…”

Section: Ulcerative Colitis Pathophysiologymentioning

confidence: 99%

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

et al. 2017

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SUMMARY Beneficial microorganisms hold promise for the treatment of numerous gastrointestinal diseases. The transfer of whole microbiota via fecal transplantation has already been shown to ameliorate the severity of diseases such as Clostridium difficile infection, inflammatory bowel disease, and others. However, the exact mechanisms of fecal microbiota transplant efficacy and the particular strains conferring this benefit are still unclear. Rationally designed combinations of microbial preparations may enable more efficient and effective treatment approaches tailored to particular diseases. Here we use an infectious disease, C. difficile infection, and an inflammatory disorder, the inflammatory bowel disease ulcerative colitis, as examples to facilitate the discussion of how microbial therapy might be rationally designed for specific gastrointestinal diseases. Fecal microbiota transplantation has already shown some efficacy in the treatment of both these disorders; detailed comparisons of studies evaluating commensal and probiotic organisms in the context of these disparate gastrointestinal diseases may shed light on potential protective mechanisms and elucidate how future microbial therapies can be tailored to particular diseases.

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Multiple Sclerosis

Pitts

Dyckman

2021

Burger's Medicinal Chemistry and Drug Discovery

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Several new medicines have been approved or entered development for the treatment of Multiple Sclerosis (MS) in the past few years. The sphingosine‐1‐phosphate (S1P) modulator fingolimod was the first FDA approved oral disease modifying therapy for MS, and it has inspired a number of additional agents directed at this clinically validated target. Fumarates (e.g. dimethyl fumarate), dihydroorotate dehydrogenase inhibitors (e.g. teriflunomide) and other agents which decrease lymphocyte proliferation (e.g. cladribine) represent additional clinically validated therapeutic approaches. While the mechanisms of action for these new agents may not be fully defined, they have demonstrated a good degree of efficacy in the treatment of relapsing forms of MS. It is of interest to note that biologic agents which target CD20 on B cells have also shown significant efficacy in the treatment of MS. This, in turn, has spurred MS clinical trials with Bruton's Tyrosine Kinase (BTK) inhibitors, which also act on B cell pathways. The introduction of each of these newer agents still requires careful consideration of the risk–benefit for individual patients, but has also set a higher bar in the treatment of MS for subsequent agents, as evidenced by the discontinuation of several agents in late stage clinical trials. This higher bar has also pushed some historic agents to second or third line agents. This speaks to an overall advancement in the treatment of MS, and provides hope for further advances in therapeutic options.

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4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

Abstract: 4SC-101 is a novel immunosuppressive drug with excellent potential for the treatment of intestinal inflammation.

Cited by 59 publications

References 34 publications

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

Multiple Sclerosis

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