Therapeutic Potential of Phosphatidylinositol 3-Kinase Inhibitors in Inflammatory Respiratory Disease

Abstract

The phosphoinositide 3-kinase(s) (PI3K) are a family of proteins that catalyze the phosphorylation of the 3-OH position of phosphoinositides and generate lipids that control a wide variety of intracellular signaling pathways. They are classified into three families according to their structure and substrate specificity and are thought to have distinct biological roles. Recent studies suggested that numerous components of the PI3K pathway play a crucial role in the expression and activation of inflammatory mediators, inflammatory cell recruitment, immune cell function, airway remodeling, and corticosteroid insensitivity in chronic inflammatory respiratory disease. Selective PI3K inhibitors have been developed that reduce inflammation and some characteristics of disease in experimental animal models. Targeting specific PI3K isoforms that may be overexpressed or overactive in disease should allow for selective treatment of respiratory diseases. Encouraging data from animal models, primary cells and clinical studies in other diseases suggest that inhibitors of PI3K/Akt may prove to be useful novel therapies in the treatment of asthma and chronic obstructive pulmonary disease.Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease (COPD), represent a profound and growing public health problem worldwide. Bronchial asthma, in addition to placing a considerable burden in terms of direct medical costs, has enormous indirect costs and is one of the leading causes of work or school absenteeism. Most patients with asthma respond well to current corticosteroid-based therapies; however, a small percentage (10%) fails to respond well and this poor control of symptoms is a major issue that can result in adverse clinical and economic outcomes (accounting for Ͼ50% of the total asthma health care costs). COPD (smoking lung) is a chronic inflammatory disease of the lower airways and lung, and this progressive and relentless loss of lung function is caused by emphysema due to destruction of lung parenchyma and by narrowing of small airways as a result of chronic inflammation Barnes and Kleinert, 2004). COPD is predicted to become the third most common cause of death and the fifth most common cause of disability in the world by 2020 (Barnes and Kleinert, 2004). Cystic fibrosis is also recognized as an inflammatory disease with increased neutrophilia, inflammatory gene expression, and enhanced activation of several transcription factors. Unfortunately, there are no effective treatments for these diseases (severe asthma and COPD and cystic fibrosis), and the molecular mechanisms underlying their pathogenesis are not fully understood. Recent research suggests that many kinases are involved in chronic airway inflammation and its This research is funded by The Wellcome Trust (UK), The Medical Research Council (UK), Associazione per la Ricerca e la Cura dell'Asma (ARCA, Padova, Italy), Chiesi Farmaceutici (Italy), GlaxoSmithKline (UK), AstraZeneca, Mitsubishi (Japan), and Pfizer (U.S...

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

“…Combination of corticosteroids or possibly more promiscuous drugs that bind to two or more of these receptors may result in an enhanced antiinflammatory profile over that seen with current corticosteroids, particularly in patients with severe disease [210]. Several key signalling pathways are involved in the inflammatory response [211,212] and also in the modulation of corticosteroid responsiveness in asthma and COPD [11,[213][214][215][216].…”

Addressing corticosteroid insensitivity in adults with asthma

“…Pre-clinical studies suggest that PI3K-δ inhibitors could potentially reverse corticosteroid insensitivity by increasing HDAC2 activity [128,129]. Selective PI3K inhibitors are being developed as novel treatments of corticosteroid insensitive airway diseases.…”

“…An inhaled PI3Kδ inhibitor GSK2269557 is undergoing clinical trials in adults with persistent uncontrolled asthma (ClinicalTrials.gov Identifier: NCT02567708). PI3K δ and γ isoforms are implicated in inflammatory cell recruitment and activation [129]. An inhaled dual PI3Kδ/γ inhibitor, TG100-115, reduces airway inflammation induced by allergen and cigarette smoke in murine models 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 and restores corticosteroid sensitivity in the smoke model [130].…”

A practical drug discovery project at the undergraduate level

“…The lead is a weakly potent (pIC 50 = 5.7), lipophilic (clogP = 3.9) and poorly soluble (< 12 g/mL, aqueous pH 7) inhibitor of one of the phosphatidylinositol-3-kinases (PI3K), which is implicated in the pathology of asthma and chronic obstructive pulmonary disease. 10 Phosphatidylinositol-3-kinases are lipid kinases whose role is to phosphorylate the 3-position hydroxyl of phosphatidylinositides. Eight different kinases are known, of which the class IA subgroup (the -, -, and -isoforms) generates phosphatidylinositol-3,4,5-triphosphate.…”