Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3Kγ Inhibitors

The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase gamma (PI3K gamma) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3K gamma offers a promising strategy in immunooncology, which has led to the development of numerous potent PI3K gamma inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3K gamma inhibition, we required a potent and PI3K gamma-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3K gamma inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3K gamma-selective inhibitors for use in immunomodulation.