Syk inhibitors in clinical development for hematological malignancies

Liu, Delong; Mamorska-Dyga, Aleksandra

doi:10.1186/s13045-017-0512-1

Cited by 150 publications

(121 citation statements)

References 96 publications

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“…(56) Thus, SYK has been a hopeful drug target for immune and inflammatory disorders, including RA and cherubism. (45,(57)(58)(59) In this study, we employed the SYK inhibitor entospletinib (GS-9973) because this second-generation compound has greater selectivity against SYK than tamatinib (R406), which is the active metabolite of fostamatinib (R788) (60)(61)(62)(63) and has a longer half-life in mouse plasma compared with R406. (61,64) Although GS-9973 has relatively high selectivity to tyrosine kinase non-receptor 1 (TNK1, Kd: TNK1 86 nM versus SYK 10.5 nM), (60,62) the most comprehensive clinical experience of SYK inhibitors to date has been obtained with GS-9973.…”

Section: Discussionmentioning

confidence: 99%

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth-supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3-domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro-CT analysis of SH3BP2-deficient (Sh3bp2 −/− ) mice challenged with ligature-induced periodontitis revealed that Sh3bp2 −/− mice develop decreased alveolar bone loss (male 14.9% AE 10.2%; female 19.0% AE 6.0%) compared with wild-type control mice (male 25.3% AE 5.8%; female 30.8% AE 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM-Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2-SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone-resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS-9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS-9973 treatment of bone marrow-derived M-CSF-dependent macrophages suppressed tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation with decreased mineral resorption capacity even when GS-9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2-SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases.

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Section: Discussionmentioning

confidence: 99%

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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“…We chose the SYK inhibitor entospletinib (GS‐9973), because this second‐generation compound has greater selectivity against SYK than tamatinib (R406), which is the active metabolite of fostamatinib (R788) (20–23) and has a longer half‐life in mouse plasma compared to R406 . Although GS‐9973 has relatively high selectivity to tyrosine kinase non‐receptor 1 (TNK1, Kd (dissociation constant): TNK1 86 nM versus SYK 10.5 nM), the most comprehensive clinical experience of SYK inhibitors to date has been obtained with GS‐9973 . GS‐9973 is currently in clinical trials for certain types of leukemia and lymphoma (https://clinicaltrials.gov).…”

Section: Resultsmentioning

confidence: 99%

Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model

Yoshimoto

Hayashi

Kondo

et al. 2018

Journal of Bone and Mineral Research

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Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for cherubism (Sh3bp2 ) develops autoinflammation resulting in systemic bone destruction. Although administration of the TNF-α blocker etanercept to neonatal Sh3bp2 mice prevented the disease onset, this therapy was not effective for adult Sh3bp2 mice or human cherubism patients who already had lesions. Because genetic ablation of spleen tyrosine kinase (SYK) in myeloid cells rescues Sh3bp2 mice from inflammation, we examined whether SYK inhibitor administration can improve fully developed cherubism symptoms in adult Sh3bp2 mice. Entospletinib (GS-9973) was intraperitoneally injected into 10-week-old Sh3bp2 mice every day for 6 weeks. Treatment with GS-9973 improved facial swelling and histomorphometric analysis of lung and liver tissue showed that GS-9973 administration significantly reduced inflammatory infiltrates associated with decreased levels of serum TNF-α. Micro-computed tomography (μCT) analysis showed that GS-9973 treatment reduced bone erosion in mandibles, calvariae, and ankle and elbow joints of Sh3bp2 mice compared to Sh3bp2 mice treated with dimethyl sulfoxide (DMSO). Taken together, the results demonstrate that administration of the SYK inhibitor ameliorates an already established cherubism phenotype in mice, suggesting that pharmacological inhibition of SYK may be a treatment option for cherubism patients with active disease progression. © 2018 American Society for Bone and Mineral Research.

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“…Current treatment usually consists of glucocorticoids, NSAIDs, DMARDs, and biologic agents, although they are not always effective and significant side effects occur. Syk inhibitors are a new group of small molecule inhibitors targeting signaling pathways (27). Although the Syk inhibitor fostamatinib (R788) has been used in clinical trials, it displays some off-target activities (27), suggesting that, newer, more selective, Syk inhibitors may be more effective.…”

Section: Discussionmentioning

confidence: 99%

“…Syk inhibitors are a new group of small molecule inhibitors targeting signaling pathways (27). Although the Syk inhibitor fostamatinib (R788) has been used in clinical trials, it displays some off-target activities (27), suggesting that, newer, more selective, Syk inhibitors may be more effective. Several new Syk inhibitors are in development and early clinical trials.…”

Section: Discussionmentioning

confidence: 99%

The role of Syk in peripheral T cells

Park

Majumdar

Brand

et al. 2018

Clinical Immunology

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The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk chimeric mice and DR1 Syk CD4 conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Syk T cells but not SykCD4 T cells. Western blots revealed a marked increase in the phosphorylation of Syk, JNK and p38 upon A12/DR1 activation in WT or Syk T cells but not in SykCD4 cells. We demonstrate that Syk is required for the APL- induction of suppressive cytokines. Chemical Syk inhibitors blocked activation of GATA-3 by peptide A12/DR1. In conclusion, this study provides novel insights into the role that Syk plays in directing T cell activity, and may shape therapeutic approaches for autoimmune diseases.

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Syk inhibitors in clinical development for hematological malignancies

Cited by 150 publications

References 96 publications

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model

The role of Syk in peripheral T cells

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