Spleen Tyrosine Kinase Inhibitor Research Articles

Spleen tyrosine kinase: a novel pharmacological target for sepsis-induced cardiac dysfunction and multi-organ failure

Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g. ventilation, dialysis), there are no specific interventions that prevent or reduce MOF in patients with sepsis. To identify possible intervention targets, we re-analyzed the publicly accessible Gene Expression Omnibus accession GSE131761 dataset, which revealed an increased expression of spleen tyrosine kinase (SYK) in the whole blood of septic patients compared to healthy volunteers. This result suggests a potential involvement of SYK in the pathophysiology of sepsis. Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis. PRT062607 or vehicle (saline) was administered to 10-weeks-old C57BL/6 mice at 1h after the onset of sepsis induced by cecal ligation and puncture (CLP). Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP. After 24h, cardiac function was assessed in vivo by echocardiography and, after termination of the experiments, serum and cardiac samples were collected to evaluate the effects of SYK inhibition on the systemic release of inflammatory mediators and the degree of organ injury and dysfunction. Our results show that treatment of CLP-mice with PRT062607 significantly reduces systolic and diastolic cardiac dysfunction, renal dysfunction and liver injury compared to CLP-mice treated with vehicle. In addition, the sepsis-induced systemic inflammation (measured as an increase in inflammatory cytokines and chemokines in the serum) and the cardiac activation of NF-kB (IKK) and the NLRP3 inflammasome were significantly reduced in CLP-mice treated with PRT062607. These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis.

Activation of spleen tyrosine kinase (SYK) contributes to neuronal pyroptosis and cognitive impairment in diabetic mice via the NLRP3/Caspase-1/GSDMD signaling pathway.

Diabetes mellitus (DM) patients are at increased risk of cognitive impairment. The precise mechanisms underlying the association between DM and cognitive impairment remain unclear. Spleen tyrosine kinase (SYK), a crucial regulator of signal transduction, has been implicated in microglial pyroptosis in experimental ischemic stroke models. The present study investigated the potential role of SYK in DM-associated cognitive impairment. Diabetes was induced by streptozotocin (STZ) in C57BL/6 mice, and cognitive function and cerebral injury were assessed 12weeks later using the Morris water maze (MWM), TUNEL assay and Western blotting. In vitro, the inhibition of SYK was investigated in a mouse hippocampal neuronal cell line cultured with high glucose. Compared with control mice, DM mice presented impaired spatial learning and memory. Additionally, SYK activation was linked to neuronal pyroptosis, as evidenced by increases in the number of TUNEL-positive cells and protein levels of NLRP3, ASC, procaspase-1, caspase-1, GSDMD, the GSDMD N-terminal fragment, pro-IL-1β, and IL-1β in the hippocampus of DM mice. Compared with no treatment, SYK knockdown markedly attenuated cognitive impairment and histologic and ultrastructural pathological changes in the hippocampus of DM mice. The increased expression of pyroptosis-associated proteins and the increased number of TUNEL-positive cells were also significantly reduced. In vitro, high glucose significantly activated SYK to trigger the canonical pyroptotic pathway in cultured HT22 cells. The inhibition of SYK with a small interfering RNA or specific inhibitor significantly ameliorated the neuronal pyroptosis mediated by high glucose. Our findings demonstrate that SYK activation plays a pivotal role in promoting the cognitive impairment associated with DM. This effect is mediated by triggering neuronal pyroptosis through the canonical NLRP3/Caspase-1/GSDMD pathway. These results suggest that SYK may serve as a potential target for preventing or mitigating cognitive impairment in patients with DM.

Fostamatinib Inhibits the Proliferation of Ovarian Cancer Cells Through Apoptosis Induction.

Ovarian cancer remains a significant challenge due to its high mortality rate and poor prognosis, especially in advanced stages. Despite treatment advancements, issues with resistance and recurrence persist, highlighting the urgent need for new and effective therapies. This study aimed to evaluate fostamatinib, an oral spleen tyrosine kinase inhibitor initially developed for autoimmune diseases, as a potential treatment for ovarian cancer. The effects of fostamatinib on ovarian cancer cell lines were assessed using WST-1 assays for cell proliferation. Apoptosis was evaluated through TUNEL assays, DNA fragmentation analysis, and flow cytometry. Western blot analysis was used to detect cleavage of apoptotic proteins, including caspase-3 and PARP, and flow cytometry analyzed cell cycle changes. Fostamatinib treatment resulted in a dose- and time-dependent reduction in ovarian cancer cell growth and induced apoptosis, as indicated by increased TUNEL-positive cells, DNA fragmentation, and rises in both early and late apoptosis. Western blot analysis showed increased cleavage of apoptotic proteins, including caspase-3 and PARP. Flow cytometry also demonstrated an increase in the sub-G1 phase of the cell cycle, further supporting apoptosis induction. Fostamatinib, by inhibiting cell proliferation and inducing apoptosis, shows promise as a repurposed therapeutic agent for ovarian cancer, potentially offering a new approach to improve patient outcomes.

Platelet Responses After Tapering and Discontinuation of Fostamatinib in Patients with Immune Thrombocytopenia: A Continuation of the Fostasur Study.

Background/objectives: Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor approved for the treatment of adult patients with chronic immune thrombocytopenia (ITP). There is little information about dose tapering and sustained remission after discontinuation in ITP. In this retrospective multicenter study, we evaluated efficacy and safety of fostamatinib in adult patients with ITP before, during, and after tapering/discontinuation (T/D). Methods: T/D was performed on subjects who achieved complete platelet response (CR) with progressive, conditional dose reduction every four weeks. Results: Sixty-one patients were included from 14 reference centers between October 2021 and May 2023. In subjects that completed T/D (n = 9), the median time from treatment initiation to response was 21 days (IQR: 7.5-42), median time from treatment initiation to CR was 28 days (IQR: 28-42), median time from treatment initiation to the start of tapering was 116 days (IQR: 42-140), and duration of tapering was 112.5 days (IQR: 94.5-191). The median platelet count was 232 × 109/L (IQR: 152-345 × 109/L) at tapering and 190 × 109/L (IQR: 142.5-316.5 × 109/L) at discontinuation. With a median follow-up since discontinuation of 263 days (IQR: 247-313 days), only two patients have relapsed (at 63 and 73 days). Fostamatinib was restarted, achieving a new CR. Platelet counts higher than 100 × 109/L in week 12 were the only positive predictive factors for successful tapering and discontinuation. Conclusions: Sustained response in patient with ITP treated with fostamatinib could be developed. The prognostic factors and recommended scheme of tapering still have to be evaluated.

Kidney injury: the spleno-renal connection and splenic tyrosine kinase.

Kidney injury is a major medical burden and one of the most common reasons for hospitalization and poor life quality. Kidney injury can include acute kidney injury, chronic kidney disease, and immune-mediated kidney diseases most of which have no definitive therapy. The spleen is a secondary lymphoid organ in the reticuloendothelial system that plays an important role in protecting the body from various diseases. Notably, spleen tyrosine kinase, a non-receptor tyrosine kinase, is a crucial player that aids in immunity and protection and is highly expressed in the kidney and hematopoietic cells. It has been shown that alterations in spleen tyrosine kinase function or expression could lead to a wide range of diseases and abnormalities. Over the past decade, the role of spleen and spleen tyrosine kinase in multiple kidney diseases has emerged. Evidence suggests that modulating the spleno-renal connection through activation of the cholinergic anti-inflammatory pathway can be a promising strategy for protecting against kidney injury. Imitating the protective function of the spleen through interleukin-10-extracellular vesicles can also be of therapeutic value. In addition, evidence showed that inhibition of the spleen tyrosine kinase leads to amelioration of the kidney injury. However, further exploration and long-term studies are needed to unravel the spleno-renal connection, as well as the efficacy of spleen tyrosine kinase inhibitors, before they can be used as means for treatment of kidney injury.

Abstract C067: Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review

Abstract Introduction: The introduction of immunotherapy, particularly programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, has transformed the treatment paradigm for non-small cell lung adenocarcinoma (NSCLC), significantly improving patient survival rates. However, alongside their immune-activating effects, these agents can also lead to immune-related adverse events (irAEs), affecting various organ systems. Among these, immune thrombocytopenia (ITP) is a rare but potentially life-threatening complication characterized by the destruction of platelets by autoantibodies, resulting in decreased platelet counts and an increased risk of bleeding. While ITP has been identified as a complication of immunotherapy, particularly PD-1 or PD-L1 inhibitors, its incidence, clinical presentation, and management remain poorly understood. Case Presentation: The 73-year-old female with stage IIIA poorly differentiated NSCLC who received chemotherapy with Taxol/Carboplatin and concurrent radiation therapy followed by a right upper lobectomy, initiated on immunotherapy with durvalumab, a PD-L1 inhibitor, developed severe thrombocytopenia (grade 4) after receiving two cycles of durvalumab. Despite steroid treatment, her condition persisted, indicating immune-related adverse events (irAEs). After confirming the diagnosis through further investigation, including molecular analysis, the patient was treated with intravenous immunoglobulin (IVIG), which significantly increased her platelet counts. Durvalumab was discontinued, and fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, was initiated to manage the irAEs effectively. Discussion: ITP is recognized as an immune-related adverse event (irAE) associated with PD-1 or PD-L1 inhibitors, although it remains rare and poorly understood. Several case reports have highlighted the occurrence of ITP induced by these inhibitors, demonstrating varied clinical presentations and responses to treatment. Mechanisms underlying ITP induction by PD-1/PD-L1 inhibitors are not fully elucidated but may involve immune dysregulation, including CD4+ and CD8+ T cell activation, production of antiplatelet antibodies, and increased expression of PD-L1 on platelets. Management strategies for ITP induced by PD-1/PD-L1 inhibitors include steroids, intravenous immunoglobulin (IVIG) therapy, recombinant human thrombopoietin (TPO), interleukin-6 (IL-6) receptor antagonists, and immunosuppressive agents. However, the effectiveness of these treatments varies among patients, highlighting the need for individualized approaches and further research to optimize management strategies. Conclusion: The prompt recognition and management of ITP induced by PD-1/PD-L1 inhibitors are essential for ensuring favorable patient outcomes. Further research is needed to understand the underlying mechanisms and develop effective prevention and management strategies for this rare but serious immune-related adverse event. Citation Format: Aliya M Khan, Richa Dawar. Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C067.

Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication.

Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and epidermal growth factor receptor (EGFR), which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both kinases with clinically available agents, this study aimed to assess the antitumor efficacy of both pharmacologic and genetic SYK and EGFR co-inhibition using a multifaceted approach to analyze the global phosphoproteome and chemoresistant ovarian cancer cell lines, patient-derived organoids, and xenograft models. Dual inhibition of SYK and EGFR in chemoresistant ovarian cancer cells elicited a highly synergistic antitumor effect. Notably, the combined inhibition strategy activated the DNA damage response, induced G1 cell cycle arrest, and promoted apoptosis. The phosphoproteomic analysis revealed that perturbation of SYK and EGFR signaling induced a significant reduction in both phosphorylated and total protein levels of cell division cycle 6 (CDC6), a crucial initiator of DNA replication. Together, this study offers preclinical evidence supporting dual inhibition of SYK and EGFR as a promising treatment for chemoresistant ovarian cancer that disrupts DNA synthesis by impairing formation of the prereplication complex. These findings warrant further clinical investigation to explore the potential of this combination therapy in overcoming drug resistance and improving patient outcomes.

Post-marketing safety surveillance of fostamatinib: an observational, pharmacovigilance study leveraging FAERS database

ABSTRACT Objective Fostamatinib, an FDA-approved oral small-molecule spleen tyrosine kinase (SYK) inhibitor, is used to treat thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have not responded to previous treatments. However, comprehensive safety data is lacking. This study uses the FDA Adverse Event Reporting System (FAERS) database to explore real-world adverse events (AEs) related to fostamatinib, aiming to inform its clinical use. Methods The FAERS database was retrospectively queried to extract reports associated with fostamatinib from 2019 to 2023. To identify and evaluate potential AEs in patients receiving fostamatinib, various disproportionality analyses such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results A total of 23 AE signals were included in our analysis. Among them, hypertension, blood pressure increase, blood pressure abnormality, hepatic enzyme increase, and diarrhea were consistent with the common AEs described for fostamatinib in clinical trials. In addition, unexpected serious AEs were detected including cerebral thrombosis and necrotizing soft tissue infection. The median time to onset of fostamatinib-related AEs was 86 days. Conclusion Our investigation revealed several possibly emergent safety concerns associated with fostamatinib in real-world clinical practice, which might provide essential vigilance evidence for clinicians and pharmacists to manage the safety issues of fostamatinib.

Fostamatinib for immune thrombocytopenic purpura in adult patients: A systematic review and meta-analysis.

Immune thrombocytopenic purpura (ITP) is an immune disorder characterized by thrombocytopenia. Fostamatinib is an orally administered spleen tyrosine kinase inhibitor intended to treat refractory ITP. To evaluate the efficacy and safety of fostamatinib as a subsequent-line therapy for ITP in adults. We searched four electronic databases for primary studies of any design. Primary efficacy outcomes included proportions of patients achieving overall (≥30×109 cells/L), partial (≥50×109 cells/L), and stable (as defined in original studies) platelet response. Safety outcomes included rescue medication use and other adverse events. We used narrative synthesis and Mantel-Haenszel random effect meta-analysis to summarize results. Our systematic review included 11 studies for analyses (n=722). Weighted mean proportions of patients achieving overall, partial, and stable responses with fostamatinib treatment were 0.70 [0.62, 0.76], 0.48 [0.36, 0.61], and 0.28 [0.16, 0.44], respectively. Fostamatinib was favored over placebo for partial (relative risk [RR]=3.04, 95% confidence interval [CI] [1.53, 6.06]) and stable (RR=6.43, 95% CI [1.58, 26.23]) responses. Patients on fostamatinib required less rescue medication and were more likely to experience hypertension. Fostamatinib is a viable subsequent-line therapy option for refractory ITP. Given the heterogeneous data and large number of small studies, these results should be interpreted cautiously.

Real-world clinical outcomes with fostamatinib for the treatment of refractory chronic immune thrombocytopenia: a single-center experience.

Fostamatinib is a spleen tyrosine kinase inhibitor indicated for the treatment of chronic immune thrombocytopenia (ITP) unresponsive to a previous treatment. Real-world studies evaluating the utilization and effectiveness of fostamatinib outside the context of a clinical trial are lacking. The objective of this analysis was to evaluate the effectiveness of fostamatinib for the treatment of ITP in a real-world cohort. We conducted a single-center, retrospective, observational study to evaluate the effectiveness of fostamatinib for the treatment of ITP. The primary endpoint was durable response as defined by the American Society of Hematology ITP response criteria. Secondary endpoints included overall response rate, time to response, and safety. Subgroup analysis was performed to assess frequency of durable response in key subgroups of patients based on prior therapies. Thirty-one patients treated with fostamatinib for ITP were included in our analysis. Patients had received a median of four prior lines of therapy. Ten patients (32%) achieved a durable response. Most durable responders maintained their response at 24 months ( n = 7; 70%). The median time to response was 9 days. Four patients (13%) discontinued fostamatinib due to an adverse event. Subgroups who had higher rates of durable responses included those who had received two to three prior lines of therapy (40%), splenectomized patients (50%), and those who had not received prior rituximab (55%). Fostamatinib therapy in a real-world population of patients with heavily pretreated ITP led to a durable response in a third of patients, which was maintained for most responders.

Efficacy and safety of sovleplenib (HMPL-523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM-01): a randomised, double-blind, placebo-controlled, phase 3 study

Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia. This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of ≥50 × 109/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open-label phase is ongoing. Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 4·0, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<0·0001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study. Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy. HUTCHMED and Science and Technology Commission of Shanghai Municipality.

Development of SYK NanoBRET Cellular Target Engagement Assays for Gain-of-Function Variants.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that is activated by phosphorylation events downstream of FcR, B-cell and T-cell receptors, integrins, and C-type lectin receptors. When the tandem Src homology 2 (SH2) domains of SYK bind to phosphorylated immunoreceptor tyrosine-based activation motifs (pITAMs) contained within these immunoreceptors, or when SYK is phosphorylated in interdomain regions A and B, SYK is activated. SYK gain-of-function (GoF) variants were previously identified in six patients that had higher levels of phosphorylated SYK and phosphorylated downstream proteins JNK and ERK. Furthermore, the increased SYK activation resulted in the clinical manifestation of immune dysregulation, organ inflammation, and a predisposition for lymphoma. The knowledge that the SYK GoF variants have enhanced activity was leveraged to develop a SYK NanoBRET cellular target engagement assay in intact live cells with constructs for the SYK GoF variants. Herein, we developed a potent SYK-targeted NanoBRET tracer using a SYK donated chemical probe, MRL-SYKi, that enabled a NanoBRET cellular target engagement assay for SYK GoF variants, SYK(S550Y), SYK(S550F), and SYK(P342T). We determined that ATP-competitive SYK inhibitors bind potently to these SYK variants in intact live cells. Additionally, we demonstrated that MRL-SYKi can effectively reduce the catalytic activity of SYK variants, and the phosphorylation levels of SYK(S550Y) in an epithelial cell line (SW480) stably expressing SYK(S550Y).

A pathological study on the efficacy of Syk inhibitors in a Candida albicans-induced aortic root vasculitis murine model

BackgroundThe activation of innate immunity may be involved in the development of Candida albicans-induced murine vasculitis, which resembles Kawasaki disease (KD) vasculitis. This study aimed to histologically clarify the time course of the development of vasculitis in this model in detail and to estimate the potential role of spleen tyrosine kinase (Syk) inhibitors in KD vasculitis. Methods and ResultsDBA/2 male mice were intraperitoneally injected with a vasculitis-inducing substance and treated with a Syk inhibitor (R788 or GS-9973). Systemic vasculitis, especially in the aortic annulus area, was histologically evaluated. Regarding lesions in the aortic annulus area, some mice in the untreated control group already showed initiation of vasculitis 1 day after the final injection of a vasculitis-inducing substance. The vasculitis expanded over time. Inflammation occurred more frequently at the aortic root than at the coronary artery. The distribution of inflammatory cells was limited to the intima, intima plus adventitia, or all layers. In the Syk inhibitor-treated groups, only one mouse had vasculitis at all observation periods. The severity and area of the vasculitis were reduced by both Syk inhibitors. ConclusionCandida albicans-induced murine vasculitis may occur within 1 day after the injection of a vasculitis-inducing substance. Additionally, Syk inhibitors suppress murine vasculitis.

A hypoxia-derived gene signature to suggest cisplatin-based therapeutic responses in patients with cervical cancer

Cervical cancer remains a significant global public health concern, often exhibits cisplatin resistance in clinical settings. Hypoxia, a characteristic of cervical cancer, substantially contributes to cisplatin resistance. To evaluate the therapeutic efficacy of cisplatin in patients with cervical cancer and to identify potential effective drugs against cisplatin resistance, we established a hypoxia-inducible factor-1 (HIF-1)-related risk score (HRRS) model using clinical data from patients treated with cisplatin. Cox and LASSO regression analyses were used to stratify patient risks and prognosis. Through qRT-PCR, we validated nine potential prognostic HIF-1 genes that successfully predict cisplatin responsiveness in patients and cell lines. Subsequently, we identified fostamatinib, an FDA-approved spleen tyrosine kinase inhibitor, as a promising drug for targeting the HRRS-high group. We observed a positive correlation between the IC50 values of fostamatinib and HRRS in cervical cancer cell lines. Moreover, fostamatinib exhibited potent anticancer effects on high HRRS groups in vitro and in vivo. In summary, we developed a hypoxia-related gene signature that suggests cisplatin response prediction in cervical cancer and identified fostamatinib as a potential novel treatment approach for resistant cases.

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors

Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors. Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n= 31; 63%), increased alanine aminotransferase (n= 26; 53%), decreased neutrophil count (n= 26; 53%), and decreased white blood cell count (n= 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4patients (9%) achieved a partial response. The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.

Real-world experience with fostamatinib in patients with immune thrombocytopenia: Results of an observational study (FORTE).

e23289 Background: Immune thrombocytopenia (ITP) is an autoantibody-mediated disease in which platelets are prematurely phagocytosed by Fcg-receptor-bearing macrophages in a spleen tyrosine kinase (SYK)-dependent signaling pathway. Corticosteroids (CS) are used to suppress the immune response, but long-term use carries a heavy burden of toxicity. Subsequent treatments for ITP include fostamatinib, a potent oral SYK inhibitor approved in 2018 based on two randomized, placebo-controlled, phase 3 trials. In trial patients, who received fostamatinib as second-line therapy following CS with or without immunoglobulins (IVIG), 25 of 32 (78%) patients achieved a platelet response of ≥50,000/µL, which was sustained for a median of 83% of treatment days. Here, we report real-world experience with fostamatinib as second-line therapy for ITP from a multi-center, prospective, observational study. Methods: The study (FORTE; NCT04904276) enrolled adult patients with ITP and an insufficient response to prior CS and/or IVIG. Patients were treated according to their clinician’s discretion, and data were collected for up to 12 months at clinic visits. Results: Sixteen patients were enrolled, and 15 were treated. Of the 15, 9 (60%) were female and the median age was 48 years (range, 20-92). 12 (80%) patients had prior CS and 6 (40%) prior IVIG. 7 (47%) patients completed the study and 8 discontinued treatment due to adverse events (4), lack of efficacy (2), and patient decision (2). After initiation of fostamatinib, 93% (14/15) of patients achieved ≥1 platelet count ≥50,000/μL. Median platelet count increased over time from 43,000/μL (IQR 19,000-105,000) at baseline to 167,000/μL (IQR 96,000-180,000) at Month 12. The median cumulative duration of elevated platelet count was 32 weeks (IQR 6.4-49.4). Concomitant CS were used by 7 (47%) patients at baseline, all of whom were able to taper as early as Month 1 and discontinue their dose by Month 3 in 4 patients, Month 6 in 2 patients, and Month 9 in 1 patient. Five patients had ITP-related AEs (4 Grade 1 and 1 Grade 2): gingival bleeding (2), mucosal haemorrhage (2), fatigue (1), contusion (3), headache (1) and epistaxis (1). There were 3 serious AEs in 2 patients: Grade 3 diarrhea in 1 and Grade 2 dyspnea and chills in 1. Overall safety results were consistent with previous studies of fostamatinib. Conclusions: Real world use of fostamatinib as documented in this observational study demonstrated efficacy and safety as second-line therapy for ITP. Fostamatinib allowed successful tapering and discontinuation of CS while maintaining platelet counts above 50,000/μL. Clinical trial information: NCT04904276 .

Spleen tyrosine kinase inhibitor R406 has both antiviral and anti-inflammatory effects on severe influenza A infection.

Death due to severe influenza is usually a fatal complication of a dysregulated immune response more than the acute virulence of an infectious agent. Although spleen tyrosine kinase (SYK) as a critical immune signaling molecule and therapeutic target plays roles in airway inflammation and acute lung injury, the role of SYK in influenza virus infection is not clear. Here, we investigated the antiviral and anti-inflammatory effects of SYK inhibitor R406 on influenza infection through a coculture model of human alveolar epithelial (A549) and macrophage (THP-1) cell lines and mouse model. The results showed that R406 treatment increased the viability of A549 and decreased the pathogenicity and mortality of lethal influenza virus in mice with influenza A infection, decreased levels of intracellular signaling molecules under the condition of inflammation during influenza virus infection. Combination therapy with oseltamivir further ameliorated histopathological damage in the lungs of mice and further delayed the initial time to death compared with R406 treatment alone. This study demonstrated that phosphorylation of SYK is involved in the pathogenesis of influenza, and R406 has antiviral and anti-inflammatory effects on the treatment of the disease, which may be realized through multiple pathways, including the already reported SYK/STAT/IFNs-mediated antiviral pathway, as well as TNF-α/SYK- and SYK/Akt-based immunomodulation pathway.

Sesamin is an effective spleen tyrosine kinase inhibitor against IgE-mediated food allergy in computational, cell-based and animal studies

Sesamin is an effective spleen tyrosine kinase inhibitor against IgE-mediated food allergy in computational, cell-based and animal studies

Drugs in Development to Treat IgA Nephropathy.

IgA nephropathy is a common glomerulonephritis consequent to the autoimmune response to aberrant glycosylated immunoglobulin (Ig) A antibodies. Although it has historically been considered a benign disease, it has since become clear that a substantial percentage of patients reach end-stage kidney failure over the years. Several therapeutic attempts have been proposed, with systemic steroids being the most prevalent, albeit burdened by possible serious adverse events. Thanks to the more in-depth knowledge of the pathogenesis of IgA nephropathy, new treatment targets have been identified and new drugs developed. In this narrative review, we summarise the molecules under clinical development for the treatment of IgA nephropathy. As a search strategy, we used PubMed, Google, ClinicalTrials.gov and abstracts from recent international congresses. TRF budesonide and sparsentan are the two molecules at a more advanced stage, just entering the market. Other promising agents are undergoing phase III clinical development. These include anti-APRIL and anti-BLyS/BAFF antibodies and some complement inhibitors. Other new possible strategies include spleen tyrosine kinase inhibitors, anti-CD40 ligands and anti-CD38 antibodies. In an era increasingly characterised by 'personalised medicine' and 'precision therapy' approaches and considering that the potential therapeutic armamentarium for IgA nephropathy will be very broad in the near future, the identification of biomarkers capable of helping the nephrologist to select the right drug for the right patient should be the focus of future studies.

The Role of Intramolecular Reactions and Chemical Degradation in the Apparent Biotransformation Pathways of a Series of SYK Inhibitors.

In vitro metabolism studies of the spleen tyrosine kinase inhibitors AZ-A and AZ-B identified four unusual metabolites. M1 (mass-to-charge ratio 411) was formed by both molecules and was common to several analogs (AZ-C to AZ-H) sharing the same core structure, appearing to derive from the complete loss of a pendent 3,4-diaminotetrahydropyran ring and pyrazole ring cleavage resulting in a nonobvious metabolite. M2-M4 were formed by AZ-A and a subset of the other compounds only and apparently resulted from a sequential loss of H2 from parent. Initial attempts to isolate M3 for identification were unsuccessful due to sample degradation, and it was subsequently found that M2 and M3 underwent sequential chemical degradation steps to M4. M4 was successfully isolated and shown by mass spectrometry and NMR spectroscopy to be a tricyclic species incorporating the pyrazole and the 3,4-diaminotetrahydropyran groups. We propose that this arises from an intramolecular reaction between the primary amine on the tetrahydropyran and a putative epoxide intermediate on the adjacent pyrazole ring, evidence for which was generated in a β-mercaptoethanol-trapping experiment. The loss of the tetrahydropyran moiety observed in M1 was found to be enhanced in an analog that was unable to undergo the intramolecular reaction step, leading us to propose two possible reaction pathways originating from the reactive intermediate. Ultimately, we conclude that the apparently complex and unusual metabolism of this series of compounds likely resulted from a single metabolic activation step forming an epoxide intermediate, which subsequently underwent intramolecular rearrangement and/or chemical degradation to form the final observed products. SIGNIFICANCE STATEMENT: The current work provides an unusual biotransformation example showing the potential for intramolecular reactions and chemical degradation to give the appearance of complex metabolism arising from a single primary route of metabolism.