tg100-115 and Inflammation

With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.

Topics: Humans; Immune System; Immunotherapy; Inflammation; Neoplasms; Protein Kinase Inhibitors

Topics: Animals; Autoimmune Diseases; B-Lymphocytes; Class Ia Phosphatidylinositol 3-Kinase; Class Ib Phosphatidylinositol 3-Kinase; Humans; Inflammation; Isoenzymes; Molecular Targeted Therapy; Neutrophils; Phosphoinositide-3 Kinase Inhibitors; Protein Conformation; T-Lymphocytes

An increasing number of studies have suggested that phosphoinositide 3-kinase-γ (PI3Kγ) and PI3Kδ are involved in the pathogenesis of autoimmune and inflammatory diseases, such as asthma and atherosclerosis. However, the underlying mechanism of acute hepatitis remains unknown. The present study aimed to determine the effect of PI3Kδ/γ inhibition on hepatic injury in a murine model of hepatitis induced by concanavalin A (ConA). It was demonstrated that the pharmacological inhibition of PI3Kδ/γ by TG100-115 did not prevent liver damage following ConA challenge. Furthermore, the PI3Kδ/γ inhibition resulted in elevated transaminase activity in the serum, aggravated hepatic lesions characterized by hepatic necrosis, increased inflammatory cell infiltration and apoptosis of hepatocytes. Survival tests demonstrated that TG100-115 significantly increased the death rate of mice following ConA challenge. In addition, TG100-115 increased the serum levels of the proinflammatory cytokine IL-2 following ConA injection. These results may oppose the development of PI3Kδ/γ inhibitors as therapeutic agents, particularly for the treatment of human hepatitis.

Topics: Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Chemical and Drug Induced Liver Injury; Class I Phosphatidylinositol 3-Kinases; Class Ib Phosphatidylinositol 3-Kinase; Concanavalin A; Cytokines; Female; Hepatitis; Hepatocytes; Humans; Immunoenzyme Techniques; Inflammation; Mice; Mice, Inbred BALB C; Mitogens; Phenols; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pteridines

Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (gamma and delta) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory PI3K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K gamma/delta inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis, a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal MI models, TG100-115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the postreperfusion time period.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Models, Molecular; Myocardial Ischemia; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Structure, Tertiary; Protein Subunits; Rats; Reperfusion Injury; Signal Transduction; Swine