pci-32765 and Virus-Diseases

Kinases are a group of therapeutic targets involved in the progression of numerous diseases, including cancer, rheumatoid arthritis, Alzheimer's disease, and viral infections. The majority of approved antiviral agents are inhibitors of virus-specific targets that are encoded by individual viruses. These inhibitors are narrow-spectrum agents that can cause resistance development. Viruses are dependent on host cellular proteins, including kinases, for progression of their life-cycle. Thus, targeting kinases is an important therapeutic approach to discovering broad-spectrum antiviral agents. As there are a large number of FDA approved kinase inhibitors for various indications, their repurposing for viral infections is an attractive and time-sparing strategy. Many kinase inhibitors, including baricitinib, ruxolitinib, imatinib, tofacitinib, pacritinib, zanubrutinib, and ibrutinib, are under clinical investigation for COVID-19. Herein, we discuss FDA approved kinase inhibitors, along with a repertoire of clinical/preclinical stage kinase inhibitors that possess antiviral activity or are useful in the management of viral infections.

Topics: Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Drug Approval; Drug Repositioning; High-Throughput Screening Assays; Humans; Protein Kinase Inhibitors; SARS-CoV-2; United States; United States Food and Drug Administration; Virus Diseases

Topics: Adenine; Aged; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Red-Cell Aplasia, Pure; Steroids; Virus Diseases

We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients (29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Bacterial Infections; Case-Control Studies; Enzyme Inhibitors; Female; Humans; Invasive Fungal Infections; Italy; Lymphoproliferative Disorders; Male; Middle Aged; Molecular Targeted Therapy; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Purines; Quinazolinones; Retrospective Studies; Risk Factors; Virus Diseases