Taking PI3Kδ and PI3Kγ One Step Ahead: Dual Active PI3Kδ/γ Inhibitors for the Treatment of Immune-Mediated Inflammatory Diseases

Abstract

The multiple roles of PI3Kdelta (p110delta) and PI3Kgamma (p110gamma) 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 p110delta and p110gamma, if not all class I PI3K isoforms, expressed and activated in leukocytes and endothelium. For example, the activity of p110delta and p110gamma 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 p110delta and p110gamma supporting the hypothesis that dual-blockade of both, p110delta and p110gamma, 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.