pci-32765 and Thrombosis

The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, more than 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton tyrosine kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared with those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (acalabrutinib and ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in severe acute respiratory syndrome coronavirus 2 infections and the suitability of its inhibitors as drugs to treat COVID-19. The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antiviral Agents; Benzamides; COVID-19; COVID-19 Drug Treatment; Humans; Lung; Molecular Targeted Therapy; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazines; Thrombosis

Bruton's tyrosine kinase (Btk) is essential for B cell differentiation and proliferation, but also platelets express Btk. Patients with X-linked agammaglobulinemia due to hereditary Btk deficiency do not show bleeding, but a mild bleeding tendency is observed in high dose therapy of B-cell malignancies with ibrutinib and novel second-generation irreversible Btk inhibitors (acalabrutinib and ONO/GS-4059). This review discusses recent studies that may explain this apparent paradox and gives mechanistic insights that suggest a unique potential of low dose irreversible Btk inhibitors as atherothrombosis-focused antiplatelet drugs.

Topics: Adenine; Administration, Oral; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Animals; Arteries; B-Lymphocytes; Benzamides; Blood Platelets; Cell Differentiation; Genetic Diseases, X-Linked; Hemorrhage; Humans; Imidazoles; Mice; Piperidines; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction; Thrombosis

The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a critical inflammatory mechanism identified in platelets, which controls platelet activation and aggregation. We have recently shown that the platelet NLRP3 inflammasome is upregulated in sickle cell disease (SCD), which is mediated by Bruton tyrosine kinase (BTK). Here, we investigated the effect of pharmacological inhibition of NLRP3 and BTK on platelet aggregation and the formation of in vitro thrombi in Townes SCD mice. Mice were injected for 4 weeks with the NLRP3 inhibitor MCC950, the BTK inhibitor ibrutinib or vehicle control. NLRP3 activity, as monitored by caspase-1 activation, was upregulated in platelets from SCD mice, which was dependent on BTK. Large areas of platelet aggregates detected in the liver of SCD mice were decreased when mice were treated with MCC950 or ibrutinib. Moreover, platelet aggregation and in vitro thrombus formation were upregulated in SCD mice and were inhibited when mice were subjected to pharmacological inhibition of NLRP3 and BTK. Targeting the NLRP3 inflammasome might be a novel approach for antiplatelet therapy in SCD.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Anemia, Sickle Cell; Animals; Blood Platelets; Disease Models, Animal; Female; Furans; Heterocyclic Compounds, 4 or More Rings; Indenes; Inflammasomes; Liver; Male; Mice, Transgenic; NLR Family, Pyrin Domain-Containing 3 Protein; Piperidines; Platelet Aggregation; Protein Kinase Inhibitors; Sulfonamides; Sulfones; Thrombosis

Pathogenic thrombus formation accounts for the etiology of many serious conditions including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Despite the development of numerous anticoagulants and antiplatelet agents, the mortality rate associated with these diseases remains high. In recent years, however, significant epidemiological evidence and clinical models have emerged to suggest that modulation of the glycoprotein VI (GPVI) platelet receptor could be harnessed as a novel antiplatelet strategy. As such, many peptidic agents have been described in the past decade, while more recent efforts have focused on the development of small molecule modulators. Herein the rationale for targeting GPVI is summarized and the published GPVI modulators are reviewed, with particular focus on small molecules. A qualitative pharmacophore hypothesis for small molecule ligands at GPVI is also presented.

Topics: Binding Sites; Biological Products; Humans; Ligands; Losartan; Molecular Dynamics Simulation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Protein Kinase Inhibitors; Signal Transduction; Small Molecule Libraries; Thrombosis

Topics: Adenine; Adult; Aged; Aged, 80 and over; Hematologic Neoplasms; Hemorrhage; Humans; Incidence; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors; Thrombosis

While efficient at treating B-cell malignancies, Bruton tyrosine kinase (BTK) inhibitors are consistently reported to increase the risk of bleeding. Analyzing platelet aggregation response to collagen in platelet-rich plasma allowed us to identify two groups in the healthy population characterized by low or high sensitivity to ibrutinib

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Blood Platelets; Humans; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Membrane Glycoproteins; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction; Thrombosis

Interaction of von Willebrand factor (VWF) with platelet glycoprotein Ib (GPIb) and interaction of collagen with GPVI are essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk), which can be blocked irreversibly by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long-term safety. We found that ibrutinib and the novel Btk inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid. Moreover, Btk inhibitors prevented platelet thrombus formation on human atherosclerotic plaque homogenate and plaque tissue sections from arterially flowing blood, whereas integrin α

Topics: Adenine; Administration, Oral; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Benzamides; Humans; Imidazoles; Male; Middle Aged; Piperidines; Plaque, Atherosclerotic; Platelet Aggregation; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Thrombosis

Topics: ADAMTS13 Protein; Adenine; Antibodies, Monoclonal; Antineoplastic Agents; Central Venous Catheters; fms-Like Tyrosine Kinase 3; Genetic Therapy; Graft vs Host Disease; Hematologic Diseases; Hemophilia B; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Multiple Myeloma; Mutation; Piperidines; Protein Kinase Inhibitors; Purpura, Thrombotic Thrombocytopenic; Pyrazoles; Pyrimidines; Recombinant Proteins; Societies, Medical; Thrombosis