idelalisib and Inflammation

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1β, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antiviral Agents; Betacoronavirus; Butyrophenones; Class I Phosphatidylinositol 3-Kinases; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Repositioning; Humans; Inflammation; Interleukin-6; Molecular Targeted Therapy; Pandemics; Peptidyl-Dipeptidase A; Piperidines; Pneumonia, Viral; Purines; Quinazolinones; SARS-CoV-2

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

Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.

Topics: Animals; Autoimmune Diseases; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Class Ib Phosphatidylinositol 3-Kinase; Clinical Trials as Topic; Humans; Inflammation; Molecular Structure; Phosphoinositide-3 Kinase Inhibitors; Protein Binding

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

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Discovery; Humans; Inflammation; Mice; Mice, Inbred DBA; Microsomes, Liver; Molecular Structure; Protein Kinase Inhibitors; Quinazolinones; Structure-Activity Relationship

Topics: Aminopyridines; Animals; Anti-Inflammatory Agents; Class Ib Phosphatidylinositol 3-Kinase; Female; Humans; Inflammation; Molecular Structure; No-Observed-Adverse-Effect Level; Protein Kinase Inhibitors; Pyrazines; Rats, Sprague-Dawley; Structure-Activity Relationship

Triggering receptor expressed on myeloid cells (TREM)-1 on polymorphonuclear neutrophils (PMN) regulates innate immune activation in infectious and non-infectious conditions. TREM-1 ligation activates phosphatidyl-inositol 3 kinase (PI3K) triggering all neutrophil effector functions. As idelalisib is a PI3K inhibitor in clinical use for the treatment of non-Hodgkin lymphomas, we asked whether this inhibitor affects PMN functionalities. We analyzed PMNs from healthy donors or lymphoma patients for oxidative burst, phagocytosis, activation markers and IL-8 release upon TREM-1 or TLR ligation ex vivo. In addition, we performed western blot analyses to characterize the signaling events inhibited by idelalisib and other PI3K inhibitors. Upon TREM-1 ligation, the oxidative burst, degranulation, L-selectin shedding and cytokine release were all strongly reduced in the presence of idelalisib along impaired phosphorylation of P38, AKT and ERK by western blot analyses. In line with this, PMNs from patients receiving idelalisib also displayed an impaired TREM-1 mediated PMN activation ex vivo. In conclusion, PI3K inhibitors might cause a neutropenia-like susceptibility to infections in patients by leading to impaired PMN functionality. This should be considered when evaluating patients for infections treated with such inhibitors in daily clinical routine.

Topics: Anti-Inflammatory Agents; Cell Count; Humans; Immunity, Innate; Inflammation; Interleukin-8; Neutrophils; Phagocytosis; Phosphatidylinositol 3-Kinases; Purines; Quinazolinones; Respiratory Burst; Signal Transduction; Triggering Receptor Expressed on Myeloid Cells-1