Design, Synthesis, and Structure–Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3‑Kinase γ (PI3Kγ)

Phosphoinositide-3-kinase γ
(PI3Kγ) is highly expressed
in immune cells and promotes the production and migration of inflammatory
mediators. The inhibition of PI3Kγ has been shown to repolarize
the tumor immune microenvironment to a more inflammatory phenotype,
thereby controlling immune suppression in cancer. Herein, we report
the structure-based optimization of an early lead series of pyrazolopyrimidine
isoindolinones, which culminated in the discovery of highly potent
and isoform-selective PI3Kγ inhibitors with favorable drug-like
properties. X-ray cocrystal structure analysis, molecular docking
studies, and detailed structure–activity relationship investigations
resulted in the identification of the optimal amide and isoindolinone
substituents to achieve a desirable combination of potency, selectivity,
and metabolic stability. Preliminary in vitro studies
indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory
cytokine gene expression in M1 macrophages.