Taking PI3Kδ and PI3Kγ one step ahead: dual active PI3Kδ/γ inhibitors for the treatment of immune-mediated inflammatory diseases.

The multiple roles of PI3Kδ (p110δ) and PI3Kγ (p110γ) in various immune cells have encouraged the development of small-molecule inhibitors of both PI3K isoforms, alone or in combination, for the treatment of immune-mediated inflamatory diseases. Recent findings suggest a previously unrecognized interdependent cooperativity between p110δ and p110γ, if not all class I PI3K isoforms, expressed and activated in leukocytes and endothelium. For example, the activity of p110δ and p110γ in combination appears to be necessary for mediating efficient (velocity and direction) trafficking of immune competent cells to sites of inflammation. This chapter will focus on the emerging evidence of the dynamic interplay of p110δ and p110γ supporting the hypothesis that dual-blockade of both, p110δ and p110γ, presents a unique therapeutic opportunity in that pharmacological inhibition of the two PI3K isoforms simultaneously may yield superior clinical results in the treatment of a variety of complex immune-mediated inflammatory diseases.