|PI3K δ/γ Inhibitors|
Phosphoinositide-3 kinases (PI3K) are critical components of the immune-cell signalling network and generate phosphatidylinositol (3,4,5) triphosphate that act as second messengers regulating downstream processes. While α and α isoforms are ubiquitous in their distribution, expression of δ and γ is restricted to hematopoetic cells and have been studies extensively in the context of immune-inflammatory disorders. While PI3K γ plays a non-redundant role in neutrophil, macrophage, and T-cell chemotaxis, maturation and migration of B-cells is exclusively governed by PI3K δ. Given their expression profiles, anomalies of PI3K δ / γ regulation are implicated in diseases arising due to abnormal immune cell expansion and/or function including immune-inflammatory conditions such as rheumatoid arthritis, fibrosis, COPD, and asthma.
Dual PI3K δ/ γ inhibition in Immuno-Inflammation
Dual δ/ γ inhibition is strongly implicated as an intervention treatment in allergic and non-allergic inflammation of the airways and autoimmune diseases manifested by a reduction in neutrophilia and TNF α in response to LPS. Scientific evidence for PI3-kinase involvement in various cellular processes underlying asthma and COPD stems from inhibitor studies and gene-targeting approaches, which makes it a potential target for treatment of respiratory disease. Resistance to conventional therapies such as corticosteroids in several patients has been attributed to an up-regulation of the PI3K pathway; thus, disruption of PI3K signaling provides a novel strategy aimed at counteracting the immuno-inflammatory response. Given the established criticality of these isoforms in immune surveillance, inhibitors specifically targeting the δ and γ isoforms would be expected to attenuate the progression of immune response encountered in most variations of airway inflammation and arthritis.
|Williams, O., et al. (2010) Chemistry & Biology. 17:123-134|
|Banham-Hall E., et al. (2012) The Open Rheumatology Journal. 6:245-258|
|Current Status : Late Pre-Clinical|