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.

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

Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3 position hydroxyl group of the inositol ring of phosphoinositide lipids (PIs) generating lipid second messengers. While alpha and beta isoforms are ubiquitous in their distribution, expression of delta and gamma is restricted to circulating hematogenous cells and endothelial cells. Unlike PI3K-alpha or beta, mice lacking expression of gamma or delta do not show any adverse phenotype indicating that targeting of these specific isoforms would not result in overt toxicity.

Dual delta/gamma inhibition is strongly implicated as an intervention strategy in allergic and non-allergic inflammation of the airways and other autoimmune diseases. Scientific evidence for PI3K-delta and gamma involvement in various cellular processes underlying asthma and COPD stems from inhibitor studies and gene-targeting approaches. Also, resistance to conventional therapies such as corticosteroids in several COPD patients has been attributed to an up-regulation of the PI3K delta/gamma pathway. Disruption of PI3K-delta/gamma signalling therefore provides a novel strategy aimed at counteracting the immuno-inflammatory response. Due to the pivotal role played by PI3K-delta and gamma in mediating inflammatory cell functionality such as leukocyte migration and activation, and mast cell degranulation, blocking these isoforms may also be an effective strategy for the treatment of rheumatoid arthritis as well.

Given the established criticality of these isoforms in immune surveillance, inhibitors specifically targeting the delta and gamma isoforms would be expected to attenuate the progression of immune response encountered in airway inflammation and rheumatoid arthritis.