Targeting phosphatidylinositol 3-kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors

Phosphatidylinositol 3-kinase gamma (PI3K gamma) has been regarded as a promising drug target for the treatment of advanced solid tumors, leukemia, lymphoma, and inflammatory and autoimmune diseases. However, the high level of structural conservation among the members of the PI3K family and the diverse physiological roles of Class I PI3K isoforms (alpha, beta, delta, and gamma) highlight the importance of isoform selectivity in the development of PI3K gamma inhibitors. In this review, we provide an overview of the structural features of PI3K gamma that influence gamma-isoform selectivity and discuss the structure-selectivity-activity relationship of existing clinical PI3K gamma inhibitors. Additionally, we summarize the experimental and computational techniques utilized to identify PI3K gamma inhibitors. The insights gained so far could be used to overcome the main challenges in development and accelerate the discovery of PI3K gamma-selective inhibitors.