Publications

The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4+T cell-priming capacity of dendritic cells

Rheumatology (Oxford). 2015;54(1):169–177

Platt AM,

Benson RA,

McQueenie R,

et al.

SYK is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors. While the clinical development of the first SYK inhibitor, fostamatinib, was stopped due to poor results in the phase 3 RA programme, there remain important questions of mechanism which may aid future developments of this target.

In these murine studies, investigators sought to gain an understanding of how the active metabolite of fostamatini...

Keywords:

• SYK,
• Preclinical

La inhibición selectiva de la tirosina quinasa esplénica (SYK) con un nuevo inhibidor de molécula pequeña biodisponible oralmente, RO9021, afecta diferentes respuestas inmunes innatas y adaptativas: implicaciones para los inhibidores de la SYK en el tratamiento de enfermedades autoinmunes

Arthritis Research and Therapy 2013 15:R146

Liao C,

Hsu J,

Kim Y et al

Spleen tyrosine kinase (SYK) has already been described as a potential therapeutic target for the treatment of autoimmune diseases. Previously the SYK inhibitor fostamatinib was in clinical development for the treatment of rheumatoid arthritis, but has since been suspended. However, investigation into SYK inhibition continues with RO2091, a novel ATP-competitive inhibitor of SYK with reasonable selectivity, potency and oral bioavailability which has been shown to suppress various innate and adap...

Keywords:

• SYK,
• Preclinical

Inhibidores de la quinasa-interruptor ‘tirosina quinasa esplénica’ en trastornos inflamatorios e inmunomediados: una revisión

European Journal of Medicinal Chemistry 2013 67:434–446

Kaur M,

Singh M,

Silakari O

SYK plays a significant role in the immune cell signalling of B cells, mast cells, macrophages and neutrophils. Kaur et al. provide a comprehensive review of the molecule, its role in autoimmune disease and clinical data on its inhibition. The paper covers the basic chemistry of SYK including structure, mechanism of action, synthetic derivatives and function, and the relevance of SYK as a therapeutic target for many autoimmune diseases is discussed. The SYK inhibitors currently in clinical trial...

Keywords:

• SYK,
• Review

Inhibidores de la quinasa: Una nueva herramienta para el tratamiento de la artritis reumatoide

Clinical Immunology 2013;148:66–78

Chakravarty SD,

Poulikakos PI,

Ivashkiv LB et al

Chakravaty et al. provide a comprehensive review of the scientific basis for kinase inhibitor use, and summarise experience from clinical trials in tofacitinib and fostamatinib, plus promising clinical data for p38-MAPK inhibitors and P13K? and P13Kd. The authors highlight potential future directions and challenges in kinase inhibitor research, including the emergence of kinases upstream of p38, such as MKK-3 and MKK-6, and the potential of BTK inhibition. One of the challenges of kinase inhibit...

Keywords:

• JAK,
• Review

Inhibición de la tirosina cinasa esplénica en el tratamiento de la artritis reumatoide

Rheumatology 2013;52:1556–1562 doi:10.1093/rheumatology/ket225

Nijjar JS,

Tindell A,

McInnes ID and Siebert S

Both the innate and adaptive immune responses are targeted by current RA treatments, but these treatments do not achieve consistent sustained disease remission. Protein kinase inhibitors represent a promising new therapeutic target, owing to their influence on downstream signalling and oral bioavailability. Fostamatinib (R788) has shown ACR20 responses of 67–72% in MTX inadequate responder patients at doses of 100mg bd and 150mg bd. However, the results in biologic non-responder patients were no...

Keywords:

• SYK,
• Phase 1,
• MOA

Farmacocinética de fostamatinib, un inhibidor de la tirosina quinasa esplénica (SYK) en sujetos humanos sanos después de su administración oral individual y múltiple en tres estudios de fase I

Br J Clin Pharmacol. 2013 Jul;76(1):78–88

Baluom M,

Grossbard EB,

Mant T,

Lau DTW

Fostamatinib (R778) is a prodrug designed to deliver the active metabolite R406 which is an inhibitor of SYK and is currently under investigation for treatment of RA. The three clinical trials, conducted in healthy subjects, included two ascending dose studies and a formulation study. The first was a single ascending dose of R406, from 80-600mg, the second was a single and multiple dose study of fostamatinib in aqueous solution with single doses from 80-400mg and multiple doses of 160mg twice da...

Keywords:

• SYK,
• Fostamatinib

Perfil de seguridad de los inhibidores de la proteína quinasa en la artritis reumatoide: revisión sistémica y meta-análisis

Ann Rheum Dis April 2013; doi:10.1136/annrheumdis-2012-203116

Salgado E,

Maneiro J,

Carmona L,

et al

Salgado and colleagues conducted a systematic literature review of the safety profiles of protein kinase inhibitors (PKis) used for the treatment of rheumatoid arthritis (RA). Additionally, the study aims included identification of any class and molecule-related target and off-target adverse events. Data from 11,858 patients across 41 publications (phase 2 and 3 studies and two pooled analyses) were analysed. As well as published trials of PKi in RA, studies on healthy individuals and patients w...

Keywords:

• JAK,
• Safety,
• Review

Enfoque en el eje SYK-BTK para el tratamiento de trastornos inmunológicos y hematológicos: progreso reciente y perspectivas terapéuticas

Pharmacol Ther. 2013 May; 138(2):294–309

Tan SL,

Liao C,

Lucas MC,

et al

This review focuses on targeting spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK) inhibitors as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders with SYK inhibition showing encouraging efficacy in patients with RA. The paper describes the role of SYK and BTK in several therapy areas including autoimmune diseases, allergic inflammatory disorders and haematological cancers as well as their role in innate immunity and regulators of adaptive...

Keywords:

• BTK,
• SYK,
• MOA,
• Review

La inflamación y erosión ósea se suprimen en modelos de artritis reumatoide después del tratamiento con un inhibidor novedoso de la Sky

Clinical Immunology 2007; 124:244-57

Pine PR,

Chang B,

Schoettler N,

et al.

This study investigated the capacity of the novel oral spleen tyrosine kinase (Syk) inhibitor R406, and its prodrug R788 (fostamatinib), to suppress the reversed passive Arthrus reaction (RPA) and collagen-induced arthritis (CIA) in rats. R406 (0.1, 1, 5 and 10 mg/kg) and R788 (10 and 30 mg/kg) reduced the cutaneous RPA reaction and inflammatory oedema in a dose-dependent manner, with statistically significant reductions in extravascular leakage and tissue swelling (72% reduction with R406 10 mg...

Keywords:

• SYK,
• Preclinical,
• Bone

Un inhibidor oral de la tirosina quinasa esplénica (Syk) para la artritis reumatoide

The New England Journal of Medicine 2010; 363(14):1303-12

Weinblatt ME,

Kavanaugh A,

Genovese MC,

et al.

This is the first phase 2 study to be published for spleen tyrosine kinase (Syk) inhibitor R788 (fostamatinib). This phase 2 study ingestigated the efficacy and safety of fostamatinib in patients with active RA despite long-term treatment with methotrexate. In this 6-month, double-blind, placebo-controlled trial, patients were randomised to receive two doses of R788 (100 mg twice daily or 150 mg once daily) or placebo once or twice daily. Significantly more patients on R788 achieved ACR 20 respo...

Keywords:

• SYK,
• Fostamatinib,
• Phase 2