Development of PI3Kγselective inhibitors:the strategies and application  

作　　者：Dong-yan Gu Meng-meng Zhang Jia Li Yu-bo Zhou Rong Sheng 

机构地区：[1]College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [2]National Center for Drug Screening,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

出　　处：《Acta Pharmacologica Sinica》2024年第2期238-247,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82003780).

摘　　要：Theγisoform 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,PI3Kγhas 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 PI3Kγinhibitors,isoform selectivity was deemed crucial.In this review,an overview of the development of PI3Kγselective 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 PI3Kγselective inhibitors.

关 键 词：PI3K PI3Kγinhibitors isoform selectivity drug development rational drug design 

分 类 号：R914[医药卫生—药物化学]