Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases

Phosphoinositol 3-kinases (PI3Ks) gamma and delta are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3K gamma and delta to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3K gamma and PI3K delta in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3K gamma delta inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.