The γ isoform of Class I PI3Ks (PI3Kγ) is primarily found in leukocytes and is essential for the function of myeloid cells, as it regulates the migration, differentiation, and activation of myeloid-lineage immune cells. Thus, PI3Kγ has been identified as a promising drug target for the treatment of inflammation, autoimmune disease, and immuno-oncology. Due to the high incidence of serious adverse events (AEs) associated with PI3K inhibitors, in the development of PI3Kγ inhibitors, isoform selectivity was deemed crucial. In this review, an overview of the development of PI3Kγ selective inhibitors in the past years is provided. The isoform selectivity of related drugs was achieved by different strategies, including inducing a specificity pocket by a propeller-shape structure, targeting steric differences in the solvent channel, and modulating the conformation of the Asp-Phe-Gly DFG motif, which have been demonstrated feasible by several successful cases. The insights in this manuscript may provide a potential direction for rational drug design and accelerate the discovery of PI3Kγ selective inhibitors.

I 类 PI3K 的 γ 亚型 (PI3Kγ) 主要存在于白细胞中，对于骨髓细胞的功能至关重要，因为它调节骨髓系免疫细胞的迁移、分化和激活。因此，PI3Kγ已被确定为治疗炎症、自身免疫性疾病和免疫肿瘤学的有前途的药物靶点。由于与 PI3K 抑制剂相关的严重不良事件 (AE) 发生率很高，因此在 PI3Kγ 抑制剂的开发中，异构体选择性被认为至关重要。本综述概述了过去几年 PI3Kγ 选择性抑制剂的发展。相关药物的亚型选择性是通过不同的策略实现的，包括通过螺旋桨形状结构诱导特异性口袋、针对溶剂通道中的空间差异以及调节Asp-Phe-Gly DFG基序的构象，这些策略已被证明通过几个成功的案例是可行的。本手稿中的见解可能为合理的药物设计提供潜在的方向，并加速 PI3Kγ 选择性抑制剂的发现。