Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors. Immune thrombocytopenia (ITP) is an autoimmune disease that usually happens when your immune system mistakenly attacks and destroys platelets, which are cells that help blood to clot. Individuals with ITP can experience easy or excessive bruising and bleeding. Scientists have identified that an enzyme called spleen tyrosine kinase (SYK) is involved in numerous biological processes that are associated with the immune system response, inflammation, and some types of cancer in humans. Therefore, it has become a target for new drugs which inhibit the action of SYK. In this review article, the authors provide a summary of the biological properties and actions of SYK and its involvement in various diseases, discuss information about drugs that have been developed as SYK inhibitors for the treatment of ITP, and consider other potential uses for drugs that inhibit SYK. Although several drugs are being developed, the only SYK inhibitor that is currently available for the treatment of ITP is a drug called fostamatinib. In patients with ITP, including those who no longer respond to other treatments, fostamatinib has been shown to improve platelet counts and reduce bleeding events. Researchers are also currently investigating the use of drugs that inhibit SYK, including fostamatinib, for the potential treatment of other diseases associated with inflammation (e.g. rheumatoid arthritis, COVID-19), autoimmunity (e.g. warm autoimmune hemolytic anemia), and blood cancers (e.g. lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia). eng

CML-466 Asciminib Provides Durable Molecular Responses in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With the T315I Mutation: Updated Efficacy and Safety Data From a Phase I Trial

CONTEXT: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib-a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket-demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). OBJECTIVE: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. DESIGN: Patients with T315I-mutated CML-CP and treated with >=1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). RESULTS: 48 patients were included;25 patients (52.1%) received >=3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients;34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for >=96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS <=1% by week 96. The safety/tolerability profile of asciminib remained favorable after =9 months of added exposure (median duration of exposure, 2.08 years;range, 0.04-4.13 years). The most common (>=10%) grade >=3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%);none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. CONCLUSIONS: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP-a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.

Effective Antiviral Activity of the Tyrosine Kinase Inhibitor Sunitinib Malate against Zika Virus.

INTRODUCTION: Zika virus (ZIKV), a mosquito-borne flavivirus, causes the outbreaks of Latin America in 2015 - 2016, with the incidence of neurological complications. Sunitinib malate, an orally bioavailable malate salt of the tyrosine kinase inhibitor, is suggested as a broad-spectrum antiviral agent against emerging viruses like severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. MATERIALS AND METHODS: This study investigated the antiviral efficacy and antiviral mechanisms of sunitinib malate against ZIKV infection using cytopathic effect reduction, virus yield, and time-of-addition assays. RESULTS: Sunitinib malate concentration-dependently reduced ZIKV-induced cytopathic effect, the expression of viral proteins, and ZIKV yield in supernatant with 50% inhibitory concentration (IC50) value of 0.015 µM, and the selectivity index of greater than 100 against ZIKV infection, respectively. Sunitinib malate had multiple antiviral actions during entry and post-entry stages of ZIKV replication. Sunitinib malate treatment at entry stage significantly reduced the levels of ZIKV RNA replication with the reduction of (+) RNA to (-) RNA ratio and the production of new intracellular infectious particles in infected cells. The treatment at post-entry stage caused a concentration-dependent increase in the levels of ZIKV (+) RNA and (-) RNA in infected cells, along with enlarging the ratio of (+) RNA to (-) RNA, but caused a pointed increase in the titer of intracellular infectious particles by 0.01 and 0.1 µM, and a substantial decrease in the titer of intracellular infectious particles by 1 µM. CONCLUSION: The study discovered the antiviral actions of sunitinib malate against ZIKV infection, demonstrating a repurposed, host-targeted approach to identify potential antiviral drugs for treating emerging and global viral diseases.

Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.