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

Abstract

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.

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

“…A ). We administered 100 mg/kg GS‐9973 intraperitoneally because this dose successfully ameliorated the established inflammation and bone destruction in cherubism mice . We found that bone loss by ligature placement was reduced by 42.1% in males and 41.6% in females in the GS‐9973 treatment group (Fig.…”

“…SYK signaling mediates diverse immune functions particularly in B cells, neutrophils, macrophages, mast cells, and osteoclasts by coupling immune cell receptors to intracellular signaling pathways . Thus, SYK has been a hopeful drug target for immune and inflammatory disorders, including RA and cherubism . 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) and has a longer half‐life in mouse plasma compared with R406 .…”

“…(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.…”

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

“… 28 , 63 , 84 Entospletinib also reduces pulmonary inflammation by macrophages and increases Treg numbers, which might mitigate the lung damage seen in the later stages of severe COVID-19. 63 , 85 , 86 In a high-content screen for mucin-1–reducing compounds, a biochemical marker predicting ARDS, fostamatinib reduced mucin-1 in vitro and in vivo. 87 However, all SYK inhibitors reduce T- and B-cell frequency and activation, potentially impairing an adequate adaptive immune response.…”

A Paradigm Shift in the Management of Cherubism? A Preliminary Report Using Imatinib

“…There also are reports of attempts at management with tumor necrosis factor-a inhibitors, calcitonin, steroids, tacrolimus, imatinib, and denosumab, with varied success. [2][3][4] This report presents 3 patients with cherubism who were managed with imatinib. All patients exhibited marked involution of their jaw lesions and improvement of dental eruption.…”