immuno inflamation
CRAC Channel Inhibitors

Calcium Release-activated calcium (CRAC) channels are a sub family of SOCs that are present on the plasma membrane and mediate several functions ranging from secretion to gene expression and cell growth. Additionally, they form a network essential for the activation of immune cells that establish the adaptive immune response. These channels open in response to depletion of endoplasmic calcium stores and are present majorly in non-excitable cells such as T-lymphocytes and mast cells. The activation of CRAC channels in the plasma membranes of these cells results in alteration in NFAT-dependent expression of several cytokines including interleukin-2. Although Interleukin-2 (IL-2) inhibitors acting through calcineurin pathway serve as potential immunosuppressive agents, they are limited by nephrotoxicity and neurotoxicity. Because localization of these channels is restricted to non-excitable cells, inhibition of calcium influx by altering CRAC channel activity is expected to be an effective and safe strategy for the treatment of autoimmune and inflammatory diseases. Furthermore, studies in subjects with non-functional CRAC channels suggest that inhibition of this target is both safe and efficacious.

Click Here For Large View Several human diseases have been linked to abnormal CRAC channel activity, including respiratory disorders, severe combined immunodeficiency (SCID) disorders, rheumatoid arthritis, inflammatory bowel disease, thrombosis and breast cancer. To date, there are few small molecules in clinical development for the treatment of rheumatoid arthritis; therefore CRAC channel inhibitors provide an exciting alternative at countering these diseases. Pharmacological suppression of CRAC channel activity reduced pro-inflammatory cytokine expression in laminar propria mononuclear cells isolated from patients with inflammatory bowel disease thereby implicating a potential therapeutic role. The contribution of CRAC channels to asthma stems from several studies in pre-clinical models wherein these channels have been shown to regulate mast cell activation and subsequent downstream effects. Drugs targeting CRAC channels could therefore be of immense clinical benefit

Parekh, A. B. (2010) Nat. Rev. Drug Discov. 9:399-410
Feske, S. (2011) Ann. N. Y. Acad. Sci. 1238: 74-90
Current Status : Late Pre-Clinical

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

Click Here For Large View 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