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.

中文翻译：

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磷酸肌醇 3-激酶 γ (PI3Kγ) 吡唑并嘧啶酰胺抑制剂的设计、合成和构效关系优化

Phosphoinositide-3-kinase γ (PI3Kγ) 在免疫细胞中高度表达并促进炎症介质的产生和迁移。已显示抑制 PI3Kγ 可将肿瘤免疫微环境重新极化为更具炎症性的表型，从而控制癌症中的免疫抑制。在此，我们报告了早期先导系列吡唑并嘧啶异吲哚啉酮的基于结构的优化，最终发现了具有良好药物样特性的高效和异构体选择性 PI3Kγ 抑制剂。X 射线共晶结构分析、分子对接研究和详细的构效关系研究确定了最佳的酰胺和异吲哚啉酮取代基，从而实现了效力、选择性和代谢稳定性的理想组合。初步的体外研究表明，用化合物56抑制 PI3Kγ通过增加 M1 巨噬细胞中促炎细胞因子基因的表达导致显着的免疫反应。