The Syk Inhibitor Fostamatinib Decreases the Severity of Colonic Mucosal Damage in a Rodent Model of Colitis

Can, Güray; Ayvaz, Süleyman; Can, Hatice; Demirtaş, Selim; Akşit, Hasan; Yılmaz, Bülent; Korkmaz, Uğur; Kurt, Mevlüt; Karaca, Turan

doi:10.1093/ecco-jcc/jjv114

Cited by 22 publications

(19 citation statements)

References 49 publications

(63 reference statements)

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“…Syk has been proposed to play a critical role in psoriasis, atherosclerosis, and IBD. The data [39] showed that Syk expression increases in experimental colitis, and fostamatinib, a Syk inhibitor, affects inflammatory cells and proinflammatory cytokines and provides histological and morphological healing of colon mucosa. MI-1 could inhibit Syk in vitro, so its anti-inflammatory effects could be realized through signaling pathways which involve Syk.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate

Kuznietsova

Yena

Kotlyar

et al. 2016

The Scientific World Journal

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In our previous studies we showed antitumor and anti-inflammatory activities of protein kinases inhibitor pyrrol derivate 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2,5-dione (MI-1) on rat colon cancer model. Therefore anti-inflammatory effect of MI-1 on rat acetic acid induced ulcerative colitis (UC) model was aimed to be discovered. The anti-inflammatory effects of MI-1 (2.7 mg/kg daily) compared to reference drug Prednisolone (0.7 mg/kg daily) after 14-day usage were evaluated on macro- and light microscopy levels and expressed in 21-grade scale. Redox status of bowel mucosa was also estimated. It was shown that in UC group the grade of total injury (GTI) was equal to 9.6 (GTIcontrol = 0). Increase of malonic dialdehyde (MDA) by 89% and protein carbonyl groups (PCG) by 60% and decrease of superoxide dismutase (SOD) by 40% were also observed. Prednisolone decreased GTI to 3 and leveled SOD activity, but MDA and PCG remained higher than control ones by 52% and 42%, respectively. MI-1 restored colon mucosa integrity and decreased mucosa inflammation down to GTI = 0.5 and leveled PCG and SOD. Thus, MI-1 possessed anti-inflammatory properties, which were more expressed that Prednisolone ones, as well as normalized mucosa redox balance, and so has a prospect for correction of inflammatory processes.

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Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate

Kuznietsova

Yena

Kotlyar

et al. 2016

The Scientific World Journal

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“…7 of the 43 candidates were published relevant to IBD. Azacitidine (DNA methyltransferase inhibitor) 51 , ISOX (HDAC inhibitor) 52 , ascorbic-acid (antioxidant) 53 , cosmosiin (cytochrome P450 inhibitor) 54 , IB-MECA (adenosine receptor agonist) 55 , fostamatinib (SYK inhibitor) 56 , and iloprost (platelet aggregation inhibitor) 57 have been used as a treatment or providing protective effects for IBD.…”

Section: Resultsmentioning

confidence: 99%

“…The adenosine receptor agonist IB-MECA was shown to alleviate inflammation in DSS-induced colitis and spontaneous colitis found in IL-10-deficient mice 55 . Fostamatinib, an SYK inhibitor, reduced the inflammatory damage in the acetic acid-induced colitis 56 . Platelet aggregation inhibitor iloprost has been demonstrated to be an antioxidant and protective against colitis induced oxidative stress in experimental colitis 57 .…”

Section: Discussionmentioning

confidence: 99%

Microbial and genetic-based framework identifies drug targets in inflammatory bowel disease

Wang¹,

Guo²,

Gao³

et al. 2021

Theranostics

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Rationale: With increasing incidence and prevalence of inflammatory bowel disease (IBD), it has become one of the major public health threats, and there is an urgent need to develop new therapeutic agents. Although the pathogenesis of IBD is still unclear, previous research has provided evidence for complex interplays between genetic, immune, microbial, and environmental factors. Here, we constructed a gene-microbiota interaction-based framework to discover IBD biomarkers and therapeutics. Methods: We identified candidate biomarkers for IBD by analyzing the publicly available transcriptomic and microbiome data from IBD cohorts. Animal models of IBD and diarrhea were established. The inflammation-correlated microbial and genetic variants in gene knockout mice were identified by 16S rRNA sequences and PCR array. We performed bioinformatic analysis of microbiome functional prediction and drug repurposing. Our validation experiments with cells and animals confirmed anti-inflammatory properties of a drug candidate. Results: We identified the DNA-sensing enzyme cyclic GMP-AMP synthase (cGAS) as a potential biomarker for IBD in both patients and murine models. cGAS knockout mice were less susceptible to DSS-induced colitis. cGAS-associated gut microbiota and host genetic factors relating to IBD pathogenesis were also identified. Using a computational drug repurposing approach, we predicted 43 candidate drugs with high potency to reverse colitis-associated gene expression and validated that brefeldin-a mitigates inflammatory response in colitis mouse model and colon cancer cell lines. Conclusions: By integrating computational screening, microbiota interference, gene knockout techniques, and in vitro and in vivo validation, we built a framework for predicting biomarkers and host-microbe interaction targets and identifying repurposing drugs for IBD, which may be tested further for clinical application. This approach may also be a tool for repurposing drugs for treating other diseases.

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“…Fostamatinib can selectively abrogate the BCR signaling pathway. Fostamatinib has potent anti-inflammatory effects [ 18 , 26 ]. It was first demonstrated to have activities in rheumatoid arthritis and immune thrombocytopenia [ 11 , 27 – 31 ].…”

Section: Syk Inhibitorsmentioning

confidence: 99%

Syk inhibitors in clinical development for hematological malignancies

2017

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Spleen tyrosine kinase (Syk) is a cytosolic non-receptor protein tyrosine kinase (PTK) and is mainly expressed in hematopoietic cells. Syk was recognized as a critical element in the B-cell receptor signaling pathway. Syk is also a key component in signal transduction from other immune receptors like Fc receptors and adhesion receptors. Several oral Syk inhibitors including fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659 are being assessed in clinical trials. The second generation compound, entospletinib, showed promising results in clinical trials against B-cell malignancies, mainly chronic lymphoid leukemia. Syk inhibitors are being evaluated in combination regimens in multiple malignancies.

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The Syk Inhibitor Fostamatinib Decreases the Severity of Colonic Mucosal Damage in a Rodent Model of Colitis

Cited by 22 publications

References 49 publications

Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate

Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate

Microbial and genetic-based framework identifies drug targets in inflammatory bowel disease

Syk inhibitors in clinical development for hematological malignancies

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