Small Molecule Inhibitors of Phosphoinositide 3-Kinase (PI3K) δ and γ

In recent years, pharmaceutical companies have increasingly focused on phosphoinositide 3-kinases delta (PI3Kδ) and gamma (PI3Kγ) as therapeutic targets for the treatment of inflammatory and autoimmune diseases. All class 1 PI3-kinases (α/β/γ/δ) generate phospholipid second messengers that help govern cellular processes such as migration, proliferation, and apoptosis. PI3K δ/γ lipid kinases are mainly restricted to the hematopoetic system whereas PI3Kα/β are ubiquitously expressed, thus raising potential toxicity concerns for chronic indications such as asthma and rheumatoid arthritis. Therefore, the challenge in developing a small molecule inhibitor of PI3K is to define and attain the appropriate isoform selectivity profile. Significant advances in the design of such compounds have been achieved by utilizing x-ray crystal structures of various inhibitors bound to PI3Kγ in conjunction with pharmacophore modeling and high-throughput screening. Herein, we review the history and challenges involved with the discovery of small molecule isoform-specific PI3K inhibitors. Recent progress in the design of selective PI3Kδ, PI3Kγ, and PI3Kδ/γ dual inhibitors will be presented.