Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors

Singh, Rajinder; Masuda, Esteban S.; Payan, Donald G.

doi:10.1021/jm201271b

Cited by 83 publications

(64 citation statements)

References 205 publications

(1,437 reference statements)

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“…SYK kinase is involved in the activation of a variety of immune cell types including macrophages, mast cells, B cells, neutrophils and dendritic cells, 41 and indeed has been suggested to function as a master regulator of Ig and FcR related cell signalling. 42 SYK kinase has been shown to play a role in B cell signalling through the B cell receptor, IgEmediated mast cell degranulation, and FcgR-mediated macrophage phagocytosis. 43 Although SYK kinase knock-out mice present with perinatal lethality and show abnormal vascular development, mice lacking SYK kinase in the haematopoietic lineage are protected from autoantibody-induced arthritis.…”

Section: Background -Syk Kinasementioning

confidence: 99%

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Complex Primary Human Cell Systems for Drug Discovery

Berg¹,

O’Mahony²

2014

Human-Based Systems for Translational Research

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Phenotypic or biofunctional assays play an important role in drug discovery by helping to bridge the gap between high-throughput, target-based screening assays used for compound identification and more physiologically relevant in vivo disease models used for preclinical development. We have developed a standardised panel of phenotypic assays using primary human cells and co-cultures that model tissue and disease biology for characterization of drug leads. Here we show application of these assays for characterisation of clinical stage kinase inhibitors for rheumatoid arthritis, the recently approved JAK kinase inhibitor, tofacitinib, and the SYK kinase inhibitor, fostamatinib. We demonstrate how profiling in this assay panel can relate to clinical effects, both efficacy and safety related.

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Section: Background -Syk Kinasementioning

confidence: 99%

“…These biological activities support the development of inhibitors of SYK kinase for asthma/allergy as well as autoimmune conditions involving B cells. 42 …”

Section: Background -Syk Kinasementioning

confidence: 99%

Complex Primary Human Cell Systems for Drug Discovery

Berg¹,

O’Mahony²

2014

Human-Based Systems for Translational Research

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“…Both the inhibitors are adenosine triphosphate (ATP)-competitive inhibitors and inhibit the kinase-activity of Syk [22]. As shown in Figure 1A, VWF, in the presence of ristocetin, induced platelet agglutination followed by a second wave of aggregation and secretion, mediated by generated thromboxane A2 (TxA2).…”

mentioning

confidence: 99%

Syk Activity Is Dispensable for Platelet GP1b-IX-V Signaling

Badolia

Kostyak

Dangelmaier

et al. 2017

IJMS

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The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation. The inhibition of Syk with the selective Syk inhibitors, OXSI-2 and PRT-060318, did not inhibit VWF-induced platelet adhesion, agglutination, aggregation, or secretion. In contrast, platelets stimulated with the Glycoprotein VI (GPVI) agonist, collagen-related peptide (CRP), failed to cause any aggregation or secretion in presence of the Syk inhibitors. Furthermore, GP1b-induced platelet signaling was unaffected in the presence of Syk inhibitors, but GPVI-induced signaling was abolished under similar conditions. Thus, we conclude that Syk kinase activity does not play any functional role downstream of GP1b-mediated platelet activation.

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“…Syk is located upstream in the cell signaling pathway, and possesses multiple phosphorylation sites, several of which serve as docking sites for downstream signaling proteins that orchestrate overall cellular process [3]. Therefore, therapies targeting Syk might be more advantageous than that acting on a single downstream event.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Benzylidene Derivatives as Potent Syk Inhibitors: Synthesis, SAR Analysis, and Biological Evaluation

Zhang

Liu

Mao

et al. 2015

Archiv der Pharmazie

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Four scaffolds of varied benzylidene derivatives were synthesized and evaluated as Syk inhibitors for the treatment of rheumatoid arthritis (RA). Among these 31 compounds, 3-benzylidene pyrrolidine-2,5-dione derivatives (including 12k) universally showed good Syk inhibitory activities in the low micromolar to submicromolar range. In the cellular profiling, compound 12k, the most efficient compound, showed excellent antiproliferative activity against fibroblast-like synoviocytes (FLS)-RA, and demonstrated potencies for suppression of IL-6 and MMP-3 secretion almost equal to R406 (positive control). The oral efficacy of 12k in the murine collagen-induced arthritis model was significant, despite being weaker than R406. Taken together, all preliminary pharmacological results supported 12k as a potential small-molecule inhibitor targeting Syk for the treatment of RA.

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Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors

Cited by 83 publications

References 205 publications

Complex Primary Human Cell Systems for Drug Discovery

Complex Primary Human Cell Systems for Drug Discovery

Syk Activity Is Dispensable for Platelet GP1b-IX-V Signaling

Discovery of Benzylidene Derivatives as Potent Syk Inhibitors: Synthesis, SAR Analysis, and Biological Evaluation

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