Designing Small Molecule PI3Kγ Inhibitors: A Review of Structure-Based Methods and Computational Approaches

The PI3K/AKT/mTOR pathway plays critical roles in a wide array of biological processes. Phosphatidylinositol 3-kinase gamma (PI3Kγ), a class IB PI3K family member, represents a potential therapeutic opportunity for the treatment of cancer, inflammation, and autoimmunity. In this Perspective, we provide a comprehensive overview of the structure, biological function, and regulation of PI3Kγ. We also focus on the development of PI3Kγ inhibitors over the past decade and emphasize their binding modes, structure-activity relationships, and pharmacological activities. The application of computational technologies and artificial intelligence in the discovery of novel PI3Kγ inhibitors is also introduced. This review aims to provide a timely and updated overview on the strategies for targeting PI3Kγ.