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Targeting phosphatidylinositol 3‐kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors
Author(s) -
Zhu Jingyu,
Li Kan,
Yu Li,
Chen Yun,
Cai Yanfei,
Jin Jian,
Hou Tingjun
Publication year - 2021
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.21770
Subject(s) - pi3k/akt/mtor pathway , gene isoform , phosphatidylinositol , kinase , computational biology , drug discovery , biology , chemistry , cancer research , pharmacology , bioinformatics , biochemistry , signal transduction , gene
Phosphatidylinositol 3‐kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of advanced solid tumors, leukemia, lymphoma, and inflammatory and autoimmune diseases. However, the high level of structural conservation among the members of the PI3K family and the diverse physiological roles of Class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. In this review, we provide an overview of the structural features of PI3Kγ that influence γ‐isoform selectivity and discuss the structure‐selectivity‐activity relationship of existing clinical PI3Kγ inhibitors. Additionally, we summarize the experimental and computational techniques utilized to identify PI3Kγ inhibitors. The insights gained so far could be used to overcome the main challenges in development and accelerate the discovery of PI3Kγ‐selective inhibitors.