Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor

Pine, Polly; Chang, Betty; Schoettler, Nathan; Banquerigo, Mona Lisa; Wang, Su; Lau, Alan F.; Zhao, Fei; Grossbard, Elliott B.; Payan, Donald G.; Brahn, Ernest

doi:10.1016/j.clim.2007.03.543

Cited by 202 publications

(196 citation statements)

References 52 publications

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“…13 In the current work, we demonstrate that Syk is overexpressed in the majority of PTCLs, despite the absence of SYK/ITK translocations in most cases. As one orally available Syk inhibitor 14 is already in clinical trial for B-cell lymphomas, Syk merits further evaluation as a possible therapeutic target in patients with PTCL as well.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

Feldman,

Sun,

Law

et al. 2008

Leukemia

131

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Peripheral T-cell lymphomas (PTCLs) are fatal in the majority of patients and novel treatments, such as protein tyrosine kinase (PTK) inhibition, are needed. The recent finding of SYK/ITK translocations in rare PTCLs led us to examine the expression of Syk PTK in 141 PTCLs. Syk was positive by immunohistochemistry (IHC) in 133 PTCLs (94%), whereas normal T cells were negative. Western blot on frozen tissue (n ¼ 6) and flow cytometry on cell suspensions (n ¼ 4) correlated with IHC results in paraffin. Additionally, western blot demonstrated that Syk-positive PTCLs show tyrosine (525/526) phosphorylation, known to be required for Syk activation. Fluorescence in situ hybridization showed no SYK/ITK translocation in 86 cases. Overexpression of Syk, phosphorylation of its Y525/526 residues and the availability of orally available Syk inhibitors suggest that Syk merits further evaluation as a candidate target for pharmacologic PTK inhibition in patients with PTCL.

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Section: Introductionmentioning

confidence: 99%

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

Feldman,

Sun,

Law

et al. 2008

Leukemia

131

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“…This was despite the fact that fostamatinib had shown a promising effect on structure in preclinical trials using animal models 44. Fostamatinib thereby joined the large number of potential RA therapeutic drugs that enter clinical development but are never approved for treatment of RA 4, 5.…”

Section: Discussionmentioning

confidence: 99%

Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis

Kjelgaard-Petersen

Platt

Braddock

et al. 2018

Arthritis & Rheumatology

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ObjectiveRheumatoid arthritis (RA) is a chronic and degenerative autoimmune joint disease that leads to disability, reduced quality of life, and increased mortality. Although several synthetic and biologic disease‐modifying antirheumatic drugs are available, there is still a medical need for novel drugs that control disease progression. As only 10% of experimental drug candidates for treatment of RA that enter phase I trials are eventually registered by the Food and Drug Administration, there is an immediate need for translational tools to facilitate early decision‐making in drug development. In this study, we aimed to determine if the inability of fostamatinib (a small molecule inhibitor of Syk) to demonstrate sufficient efficacy in phase III of a previous clinical study could have been predicted earlier in the development process.MethodsBiomarkers of bone, cartilage, and interstitial matrix turnover (C‐telopeptide of type I collagen [CTX‐I], matrix metalloproteinase–derived types I, II, and III collagen neoepitopes [C1M, C2M, and C3M]) were measured in 450 serum samples from the Oral Syk Inhibition in Rheumatoid Arthritis 1 study (OSKIRA‐1, a phase III clinical study of the efficacy of fostamatinib in RA) at baseline and follow‐up. Additionally, the same biomarkers were subsequently measured in conditioned media from osteoclast, cartilage, and synovial membrane cultured with the active metabolite of fostamatinib, R406, to assess the level of suppression induced by the drug.ResultsIn OSKIRA‐1 serum samples and osteoclast and cartilage cultures, fostamatinib suppressed the levels of CTX‐I and C2M. In OSKIRA‐1 serum samples and synovial membrane cultures, fostamatinib did not mediate any clinical or preclinical effect on either C1M or C3M, which have previously been associated with disease response and efficacy.ConclusionThese data demonstrate that translational biomarkers are a potential tool for early assessment and decision‐making in drug development for RA treatment.

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“…Thus, the finding that Cb1 ubiquitin ligase, an enzyme critical for providing a signal for protein degradation, was a negative regulator of SyK ubiquitination and degradation, also made the polyubiquitination-proteasome pathway (see below) a relevant drug target for RA [13]. Of note, Pine et al [14] previously showed that R788, a prodrug of the active novel SyK inhibitor, R406, suppressed the severity of arthritis, subchondral bone erosion, development of pannus and synovitis in the collagen-induced arthritis (CIA) model of RA in mice thus, spurring on the development of SyK inhibitors for testing their efficacy in RA clinical trials. Furthermore, inhibition of SyK by R406 resulted in suppressed levels of synovial cytokines and serum levels of cartilage oligomeric matrix protein.…”

Section: Spleen Tyrosine Kinase (Syk)mentioning

confidence: 99%

Investigative Drugs for Rheumatoid Arthritis: Novel Targets

Malemud¹

2016

J Autoimmune Disord

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Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor

Cited by 202 publications

References 52 publications

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis

Investigative Drugs for Rheumatoid Arthritis: Novel Targets

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